Neural tube formation in which week of pregnancy

En. oki. pp. ua – all the girls have to know

Tips for pregnant women and new mothers

4 week four of pregnancy

The fourth week of pregnancy — delay monthly for 2 weeks now and this is the main symptom of pregnancy and symptoms of pregnancy may not be apart of subfebrile temperature and uncertain feelings, uterine size less than a hen’s egg.

Pregnancy can be determined according to the test, the level of hCG and ultrasound.

Symptoms and sensations at 4 weeks of pregnancy

The fourth week of a characteristic sign of pregnancy — is the delay period. Sometimes there is a weakness, malaise, or low-grade fever (up to 37,5 °).

The fourth week of a woman may feel chest high sensitivity and a nagging pain in the abdomen. Mood swings can also disturb the future mother. In rare cases, this period begins toxicosis.

Basically feeling uncertain. It’s small enough time for major changes in health.

Fetation week four of pregnancy

By the middle of 4 weeks of pregnancy the embryo length 4 mm, already have heart rate.

Begins the formation of the umbilical cord, which necessarily contains two arteries and veins 2, right Vienna gradually closed. The dimensions of the embryo are very small, but it already has the beginnings of the nervous system, respiratory organs, limbs, eyes, nose. At this stage, the embryo is still there and gills.

The fourth week of the intestinal tube begins to form. From this stage of development of the fetus begins organogenesis. The fourth week — the period of formation of the nervous system. By the end of the week the fetus already has segments of spinal cord and brain. At the same time begins the formation of the respiratory and urinary system. Fetus there are two primary germ lung and kidney.

In addition to the gonads and neural tube in the embryo on ultrasound is already clearly visible limb buds and the region pulsating heart. The heart rate reached 130 beats per minute. An alarm — fetal heart rate of 100 and below. Especially if during this period the woman appeared allocation and low-grade fever.

The embryo is very fast growing and developing. On the fourth week of his brain takes up half of the neural tube, and by the end of this week are beginning to form spinal nerves and knots. In the brain, formed the beginnings of the hypothalamus.

Fetal heart has two chambers. By the end of the week there arises septum and thickening tissue from which will be formed in future atrio-ventricular valves. At this stage, the embryo has still gills. Holes gill slits in the future will give rise to the development of the middle ear, thyroid and parathyroid glands, nose, eyes.

Power to the 4th week

The most important trace element in the fourth week — folic acid. It reduces the risk of malformations of the nervous system, helps to correct formation of most organs and systems. From this week, a woman should give up coffee and strong tea.

The main way to prevent fetal malformation is correction vitaminodefitsitnogo condition of the woman. Prescribe vitamins for pregnant women.

For the normal development of the embryo and tissue regulation of tissue differentiation in the diet is introduced foods rich in vitamin A: beef liver, eggs, wild rose, apricots, tomatoes, bell peppers, spinach, celery, parsley.

For the metabolism of folic acid and iron in the mother useful products containing vitamin C: berries, citrus fruits, walnuts. Vitamin C strengthens blood vessels and has a positive effect on the rheological properties of the blood of the mother.

For the proper formation of the fetal lung tissue helpful foods rich in vitamin E: unrefined vegetable oil, wheat germ, or rye. Vitamin E is included in the composition of cell membranes and acts as an antioxidant.

If a pregnant woman comes early toxicosis, it is useful to eat foods rich in vitamin H (biotin): peas, nuts, oatmeal, egg yolk, beef liver. However, expectant mothers should know that a large amount of fat-soluble vitamins (A, E, D) can have a toxic effect on the fetus.

4 Vitamin H (Biotin)

Complex vitamins

Lack or excess of vitamin C can cause abortion. Lack of vitamin B6 affects the occurrence of early abortion. Pregnant useful to include in the diet products from wheat flour, unrefined cereals, pomegranates.

Uzi in the fourth week of pregnancy

On US heart rate of 110-130 beats / min, if the heart rate This entry was posted in 1. Pregnancy and childbirth, Pregnancy Calendar for weeks on 14.02.2015 by administr.

NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000.

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Developmental Biology. 6th edition.

Formation of the Neural Tube

There are two major ways of forming a neural tube. In Primary neurulation, the cells surrounding the neural plate direct the neural plate cells to proliferate, invaginate, and pinch off from the surface to form a hollow tube. In Secondary neurulation, the neural tube arises from a solid cord of cells that sinks into the embryo and subsequently hollows out (cavitates) to form a hollow tube. The extent to which these modes of construction are used varies among vertebrate classes. Neurulation in fishes is exclusively secondary. In birds, the anterior portions of the neural tube are constructed by primary neurulation, while the neural tube caudal to the twenty-seventh somite pair (i. e., everything posterior to the hindlimbs) is made by secondary neurulation (Pasteels 1937; Catala et al. 1996). In amphibians, such as Xenopus, most of the tadpole neural tube is made by primary neurulation, but the tail neural tube is derived from secondary neurulation (Gont et al. 1993). In mice (and probably humans, too), secondary neurulation begins at or around the level of somite 35 (Schoenwolf 1984; Nievelstein et al. 1993).

Primary neurulation

The events of primary neurulation in the chick and the frog are illustrated in Figures 12.3 and 12.4, respectively. During primary neurulation, the original ectoderm is divided into three sets of cells: (1) the internally positioned neural tube, which will form the brain and spinal cord, (2) the externally positioned epidermis of the skin, and (3) the neural crest cells. The neural crest cells form in the region that connects the neural tube and epidermis, but then migrate elsewhere; they will generate the peripheral neurons and glia, the pigment cells of the skin, and several other cell types.

Figure 12.3

Primary neurulation: neural tube formation in the chick embryo. (A, 1) Cells of the neural plate can be distinguished as elongated cells in the dorsal region of the ectoderm. Folding begins as the medial neural hinge point (MHP) cells anchor to notochord (more. )

Figure 12.4

Three views of neurulation in an amphibian embryo, showing early (left), middle (center), and late (right) neurulae in each case. (A) Looking down on the dorsal surface of the whole embryo. (B) Sagit-tal section through the medial plane of the embryo. (more. )

VADE MECUM

Chick Neurulation. By 33 hours of incubation, neurulation in the chick embryo is well underway. Both whole mounts and a complete set of serial cross sections through a 33-hour chick embryo are included in this segment so that you can see this amazing event. The serial sections can be displayed either as a continuum in movie format or individually, along with labels and color-coding that designates germ layers. [Click on Chick-Mid]

The process of primary neurulation appears to be similar in amphibians, reptiles, birds, and mammals (Gallera 1971). Shortly after the neural plate has formed, its edges thicken and move upward to form the Neural folds, while a U-shaped Neural groove appears in the center of the plate, dividing the future right and left sides of the embryo (see Figures 12.2C and 12.3). The neural folds migrate toward the midline of the embryo, eventually fusing to form the neural tube beneath the overlying ectoderm. The cells at the dorsalmost portion of the neural tube become the Neural crest cells.

Neurulation occurs in somewhat different ways in different regions of the body. The head, trunk, and tail each form their region of the neural tube in ways that reflect the inductive relationship of the pharyngeal endoderm, prechordal plate, and notochord to its overlying ectoderm (Chapters 10 and 11). The head and trunk regions both undergo variants of primary neurulation, and this process can be divided into four distinct but spatially and temporally overlapping stages: (1) formation of the neural plate; (2) shaping of the neural plate; (3) bending of the neural plate to form the neural groove; and (4) closure of the neural groove to form the neural tube (Smith and Schoenwolf 1997; see Figure 12.2).

Formation and shaping of the neural plate

The process of neurulation begins when the underlying dorsal mesoderm (and pharyngeal endoderm in the head region) signals the ectodermal cells above it to elongate into columnar neural plate cells (Smith and Schoenwolf 1989; Keller et al. 1992 ). Their elongated shape distinguishes the cells of the prospective neural plate from the flatter pre-epidermal cells surrounding them. As much as 50% of the ectoderm is included in the neural plate. The neural plate is shaped by the intrinsic movements of the epidermal and neural plate regions. The neural plate lengthens along the anterior-posterior axis, narrowing itself so that subsequent bending will form a tube (instead of a spherical capsule).

In both amphibians and amniotes, the neural plate lengthens and narrows by convergent extension, intercalating several layers of cells into a few layers. In addition, the cell divisions of the neural plate cells are preferentially in the Rostral-caudal (beak-tail; anterior-posterior) direction (Jacobson and Sater 1988; Schoenwolf and Alvarez 1989; Sausedo et al. 1997; see Figures 12.2 and 12.3). These events will occur even if the tissues involved are isolated. If the neural plate is isolated, its cells converge and extend to make a thinner plate, but fail to roll up into a neural tube. However, if the “border region” containing both presumptive epidermis and neural plate tissue is isolated, it will form small neural folds in culture (Jacobson and Moury 1995; Moury and Schoenwolf 1995).

12.1 Formation of the floor plate cells. One of the major controversies in developmental neurobiology concerns the origin of the cells that form the ventral floor of the neural tube. It is possible that these cells are derived directly from the notochord and do not arise from the surface ectoderm. http://www. devbio. com/chap12/link1201.shtml

Bending of the neural plate

The bending of the neural plate involves the formation of Hinge regions where the neural tube contacts surrounding tissues. In these regions, the presumptive epidermal cells adhere to the lateral edges of the neural plate and move them toward the midline (see Figure 12.3B). In birds and mammals, the cells at the midline of the neural plate are called the Medial hinge point (MHP) Cells. They are derived from the portion of the neural plate just anterior to Hensen’s node and from the anterior midline of Hensen’s node (Schoenwolf 1991a, b; Catala et al. 1996). The MHP cells become anchored to the notochord beneath them and form a hinge, which forms a furrow at the dorsal midline. The notochord induces the MHP cells to decrease their height and to become wedge-shaped (van Straaten et al. 1988; Smith and Schoenwolf 1989). The cells lateral to the MHP do not undergo such a change (Figures 12.3B, C). Shortly thereafter, two other hinge regions form furrows near the connection of the neural plate with the remainder of the ectoderm. These regions are called the Dorsolateral hinge points (DLHPs), and they are anchored to the surface ectoderm of the neural folds. These cells, too, increase their height and become wedge-shaped.

Cell wedging is intimately linked to changes in cell shape. In the DLHPs, microtubules and microfilaments are both involved in these changes. Colchicine, an inhibitor of microtubule polymerization, inhibits the elongation of these cells, while cytochalasin B, an inhibitor of microfilament formation, prevents the apical constriction of these cells, thereby inhibiting wedge formation (Burnside 1973; Karfunkel 1972; Nagele and Lee 1987). After the initial furrowing of the neural plate, the plate bends around these hinge regions. Each hinge acts as a pivot that directs the rotation of the cells around it (Smith and Schoenwolf 1991).

Meanwhile, extrinsic forces are also at work. The surface ectoderm of the chick embryo pushes toward the midline of the embryo, providing another motive force for the bending of the neural plate (see Figure 12.3C; Alvarez and Schoenwolf 1992). This movement of the presumptive epidermis and the anchoring of the neural plate to the underlying mesoderm may also be important for ensuring that the neural tube invaginates into the embryo and not outward. If small pieces of neural plate are isolated from the rest of the embryo (including the mesoderm), they tend to roll inside out (Schoenwolf 1991a). The pushing of the presumptive epidermis toward the center and the furrowing of the neural tube creates the neural folds.

Closure of the neural tube

The neural tube closes as the paired neural folds are brought together at the dorsal midline. The folds adhere to each other, and the cells from the two folds merge. In some species, the cells at this junction form the neural crest cells. In birds, the neural crest cells do not migrate from the dorsal region until after the neural tube has been closed at that site. In mammals, however, the cranial neural crest cells (which form facial and neck structures) migrate while the neural folds are elevating (i. e., prior to neural tube closure), whereas in the spinal cord region, the crest cells wait until closure has occurred (Nichols 1981; Erickson and Weston 1983).

The closure of the neural tube does not occur simultaneously throughout the ectoderm. This is best seen in those vertebrates (such as birds and mammals) whose body axis is elongated prior to neurulation. Figure 12.5 depicts neurulation in a 24-hour chick embryo. Neurulation in the Cephalic (head) region is well advanced, while the Caudal (tail) region of the embryo is still undergoing gastrulation. Regionalization of the neural tube also occurs as a result of changes in the shape of the tube. In the cephalic end (where the brain will form), the wall of the tube is broad and thick. Here, a series of swellings and constrictions define the various brain compartments. Caudal to the head region, however, the neural tube remains a simple tube that tapers off toward the tail. The two open ends of the neural tube are called the Anterior neuropore and the Posterior neuropore.

Figure 12.5

Stereogram of a 24-hour chick embryo. Cephalic portions are finishing neurulation while the caudal portions are still undergoing gastrulation. (From Patten 1971; after Huettner 1949.)

Unlike neurulation in chicks (in which neural tube closure is initiated at the level of the future midbrain and “zips up” in both directions), neural tube closure in mammals is initiated at several places along the anterior-posterior axis (Golden and Chernoff 1993; Van Allen et al. 1993). Different Neural tube defects are caused when various parts of the neural tube fail to close (Figure 12.6). Failure to close the human Posterior neural tube regions at day 27 (or the subsequent rupture of the posterior neuropore shortly thereafter) results in a condition called Spina bifida, the severity of which depends on how much of the spinal cord remains exposed. Failure to close the Anterior neural tube regions results in a lethal condition, Anencephaly. Here, the forebrain remains in contact with the amniotic fluid and subsequently degenerates. Fetal forebrain development ceases, and the vault of the skull fails to form. The failure of the entire neural tube to close over the entire body axis is called Craniorachischisis. Collectively, neural tube defects are not rare in humans, as they are seen in about 1 in every 500 live births. Neural tube closure defects can often be detected during pregnancy by various physical and chemical tests.

Figure 12.6

Neurulation in the human embryo. (A) Dorsal and transverse sections of a 22-day human embryo initiating neurulation. Both anterior and posterior neuropores are open to the amniotic fluid. (B) Dorsal view of a neurulating human embryo a day later. The (more. )

Human neural tube closure requires a complex interplay between genetic and environmental factors. Certain genes, such as Pax3, Sonic hedgehog, and Openbrain, are essential for the formation of the mammalian neural tube, but dietary factors, such as cholesterol and folic acid, also appear to be critical. It has been estimated that 50% of human neural tube defects could be prevented by a pregnant woman’s taking supplemental folic acid (vitamin B12), and the U. S. Public Health Service recommends that all women of childbearing age take 0.4 mg of folate daily to reduce the risk of neural tube defects during pregnancy (Milunsky et al. 1989; Czeizel and Dudas 1992; Centers for Disease Control 1992).

The neural tube eventually forms a closed cylinder that separates from the surface ectoderm. This separation is thought to be mediated by the expression of different cell adhesion molecules. Although the cells that will become the neural tube originally express E-cadherin, they stop producing this protein as the neural tube forms, and instead synthesize N-cadherin and N-CAM (Figure 12.7). As a result, the surface ectoderm and neural tube tissues no longer adhere to each other. If the surface ectoderm is experimentally made to express N-cadherin (by injecting N-cadherin mRNA into one cell of a 2-cell Xenopus embryo), the separation of the neural tube from the presumptive epidermis is dramatically impeded (Detrick et al. 1990; Fujimori et al. 1990).

Figure 12.7

Expression of N-cadherin and E-cadherin adhesion proteins during neurulation in Xenopus. (A) Normal development. In the neural plate stage, N-cadherin is seen in the neural plate, while E-cadherin is seen on the presumptive epidermis. Eventually, the (more. )

12.2 Neural tube closure. The closing of the neural tube is a complex event that can be influenced by both genes and environment. The interactions between genetic and environmental factors are now being untangled. http://www. devbio. com/chap12/link1202.shtml

Secondary neurulation

Secondary neurulation involves the making of a Medullary cord and its subsequent hollowing into a neural tube (Figure 12.8). Knowledge of the mechanisms of secondary neurulation may be important in medicine, given the prevalence of human posterior spinal cord malformations.

Figure 12.8

Secondary neurulation in the caudal region of a 25-somite chick embryo. (A) The medullary cord forming at the most caudal end of the chick tailbud. (B) The medullary cord at a slightly more anterior position in the tailbud. (C) The neural tube is cavitating (more. )

In frogs and chicks, secondary neurulation is usually seen in the neural tube of the lumbar (abdominal) and tail vertebrae. In both cases, it can be seen as a continuation of gastrulation. In the frog, instead of involuting into the embryo, the cells of the dorsal blastopore lip keep growing ventrally (Figure 12.9A, B). The growing region at the tip of the lip is called the Chordoneural hinge (Pasteels 1937), and it contains precursors for both the posteriormost portion of the neural plate and the posterior portion of the notochord. The growth of this region converts the roughly spherical gastrula, 1.2 mm in diameter, into a linear tadpole some 9 mm long. The tip of the tail is the direct descendant of the dorsal blastopore lip, and the cells lining the blastopore form the Neurenteric canal. The proximal part of the neurenteric canal fuses with the anus, while the distal portion becomes the Ependymal canal (i. e., the lumen of the neural tube) (Figure 12.9C; Gont et al. 1993).

Figure 12.9

Movements of cells during secondary neurulation in Xenopus. (A) Involution of the mesoderm at the mid-gastrula stage. (B) Movements of the dorsal blastopore lip at the late gastrula/early neurula stage. Involution has ceased, and both the ectoderm and (more. )

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Neural Tube Defects

Dr Adrian Bonsall, 21 Jul 2014

Patient professional reference

Professional Reference articles are written by UK doctors and are based on research evidence, UK and European Guidelines. They are designed for health professionals to use. You may find the Spina Bifida article more useful, or one of our other Health articles.

In this article

  • Arrow-downEpidemiology
  • Arrow-downPresentation and management
  • Arrow-downInvestigations
  • Arrow-downPrenatal screening
  • Arrow-downManagement
  • Arrow-downComplications
  • Arrow-downPrognosis
  • Arrow-downPrevention

Neural Tube Defects

In this article

Neural tube defects (NTDs) are the second most common severe disabling human congenital defects. [1] Causation of NTDs involves multiple genes, and nutritional and environmental factors.

Neural tube is the embryonic precursor of the brain and spinal cord. The process of neural tube formation is complex, in which a flat sheet of thickened ectodermal cells (neural plate) is converted into a tube. The fusion of the neural tube occurs early in pregnancy from day 21 to day 28 after conception. Abnormal closure of the neural plate results in NTDs. [1] NTDs can be classified as:

  • Open: frequently involve the entire central nervous system; neural tissue is exposed with associated leakage of cerebrospinal fluid (CSF).
  • Closed: localised and confined to the spine with the brain rarely affected; neural tissue is not exposed although the skin covering the defect may be dysplastic.

NTDs can be classified on the basis of site of involvement (cranial and spinal) or into open (neural tissue exposed) or closed (neural tissue not exposed).

Cranial NTDs

  • Anencephaly.
  • Encephalocele (meningocele or meningomyelocele).
  • Congenital dermal sinus.

Spinal NTDs

  • Spina bifida.
  • Spina bifida occulta.
  • Myelomeningocele.
  • Meningocele.
  • Congenital dermal sinus.
  • Caudal agenesis.

Epidemiology [2]

  • Incidence has declined significantly in a period of 30 years and now occurs in approximately 0.8/1,000 total births.
  • Anencephaly and spina bifida account for up to 95% of all NTDs with equal prevalence.

Risk factors

  • Family history: one type of malformation puts other family members at risk of all types of defect.
  • May occur as part of a number of different syndromes and chromosomal disorders.
  • Inadequate folate which may be due to inadequate intake, use of folic acid antagonists (eg, methotrexate) or genetic factors causing abnormal folate metabolism.
  • Therapy with anti-epileptic drugs (sodium valproate, carbamazepine).
  • Dysraphism is used to describe situations where there is continuity between the posterior neuroectoderm and cutaneous ectoderm.

Presentation and management [3]

Cranial dysraphism

  • Exencephaly:
    • Cranium (entire or significant portion) is absent but brain tissue is present.
    • Considered as embryologic predecessor of anencephaly. [4]
  • Anencephaly:
    • Cranial vault is absent.
    • Most cases are now terminated following prenatal diagnosis.
    • Up to 75% of the anencephalic fetuses are stillborn with the remainder dying shortly after birth. [5]
    • In live born babies, initial neurological examination may appear normal if brainstem structures are relatively intact and there may be seizures despite lack of cerebral hemispheres.
  • Cephaloceles:
    • Brain matter herniates through a defect in skull. A cranial meningocele contains only meninges; an encephalocele contains brain tissue; a ventriculocele contains part of the ventricle within the herniated part of the brain.
    • These are rarer than anencephaly or spina bifida, with an incidence of 1-3/10,000 live births.
    • Associated with other brain abnormalities – eg, agenesis of corpus callosum or abnormal gyration – and may be part of a recognised syndrome.
    • Posterior cephaloceles are most common in western countries with most being occipital encephaloceles of variable size occurring above or below the tentorium. If below, they are associated with severe cerebellar defects – eg, Chiari III malformation.
    • Depending on size, site and associated abnormalities, there may be visual, sensorimotor disturbance, intellectual impairment and seizures.
    • In some parts of Asia, anterior cephaloceles are more common and may protrude into the nose, ethmoid or orbit. They often include olfactory tissue and frontal lobe tissue.
    • Cephalocele usually occurs as an isolated lesion but may be part of a syndrome such as Meckel-Gruber or Walker-Warburg syndrome. [6]

Spinal dysraphism

Spina bifida includes spina bifida occulta and spina bifida cystica. Spina bifida occulta is the most common form of spina bifida with isolated laminar defects being seen in 5% of spinal X-rays. Neurological deficit is rare and the only clinical sign is a tuft of hair or dimple at the site of defect. [7]

Spina bifida cystica may be either a meningocele without neural tissue or a myelomeningocele where the spinal cord forms part of the cyst wall.

  • Meningocele:
    • Protrusion of the meninges outside the spinal canal accounts for 5% of cases of spina bifida cystica.
    • There is no associated hydrocephalus, and neural examination is often normal.
  • Myelomeningocele:
    • Occurs in 80-90% of spina bifida cystica cases.
    • 80% are lumbosacral consisting of a sac covered with a thin membrane that may leak CSF.
    • The level of lesion is best assessed by determining the upper limit of sensory loss; however, at all levels there is disturbance of bladder and bowel control.
    • Higher lesions are associated with bladder outlet obstruction with consequent dilatation of the upper urinary tract, and chronic pyelonephritis.
    • Hydrocephalus occurs in approximately 90% of cases at birth, even with normal head circumference.
    • It is usually associated with Chiari II malformation but it may also be due to aqueduct stenosis or have no clear cause.
    • It is usually detected by ultrasound.
    • If there are signs of progressive ventricular dilatation or rising intracranial pressure, there is usually a need for insertion of a ventriculoperitoneal shunt.
  • Chiari II malformation:
    • Occurs in approximately 70% of cases of myelomeningocele.
    • It consists of downward protrusion of the medulla below the foramen magnum to overlap the spinal cord.
    • This causes the medulla to be kinked and the cerebellar vermis indented, the fourth ventricle elongated and the midbrain distorted.
    • Problems include palsies and central apnoea.
    • Treatment by closure of the defect remains controversial and is not always performed.
  • Spina bifida occulta:
    • A defect of the posterior arch of one or more lumbar or sacral vertebrae (often L5 and S1).
    • It is often found incidentally on X-ray in children admitted to hospital; it may be considered as a normal variant.
    • However, if examination reveals a naevus, hairy patch, dimple, sinus or subcutaneous mass, MRI scan of the spinal cord is recommended even if there are no associated problems with sphincter or limb control.
    • It can cause asymmetrical lower motor neurone weakness associated with wasting, deformity and diminished reflexes.
    • There may also be progressive gait disturbance with spasticity and impaired bladder control.
  • Dorsal dermal sinuses:
    • Often found in the occipital and lumbosacral areas and can connect the skin surface to the dura or to an intradural dermoid cyst.
    • If open, it can produce recurrent meningitis so should be explored and removed if possible, before infection occurs.
  • Lipomyelomeningocele:
    • Seen as a bulge in the lumbosacral region normally lateral to the midline.
    • This is a lipoma or lipofibroma attached to the spinal cord, which is low-lying.
    • They are often associated with a meningocele.
  • Diastematomyelia:
    • Sagittal cleft dividing the spinal cord into two halves, each surrounded by its pia mater.
    • The cord may be transfixed by a bony or cartilaginous spur.
    • Usually occurs in the low thoracic or lumbar regions.
    • Overlying skin abnormality is present in 75% of cases and X-rays show abnormalities in most cases, including abnormal segmentation of vertebrae, spina bifida and scoliosis.
    • Neurosurgery is normally indicated if abnormality involves cord or nerve roots, with the objective of freeing spinal cord from abnormal attachment to allow for normal growth and prevent further damage.

Investigations

  • MRI is the study of choice for imaging neural tissue and for identifying contents of the defect in the newborn.
  • CT scan allows direct visualisation of the bony defect and anatomy.
  • Ultrasound is used antenatally for screening.

Prenatal screening

  • Prenatal screening is possible by measurement of maternal serum alpha-fetoprotein or ultrasound
  • Alpha-fetoprotein in maternal serum: it is best detected at 16-18 weeks of pregnancy but may not detect closed defects and is less sensitive in women taking valproate.
  • Ultrasound: is an effective technique for detecting NTDs and detects more NTDs than serum alpha-fetoprotein. [8] It can detect anencephaly from the 12th week and spina bifida from 16-20 weeks (may occasionally be missed, especially in the L5-S2 region).
  • Second-trimester ultrasound examination increases detection rate of spina bifida to 92-95% and detection of anencephaly to 100%. [9]
  • Amniocentesis: this is only used when it has not been possible to obtain adequate ultrasound images; it is used to measure alpha-fetoprotein and neuronal acetylcholinesterase.

Management

  • Affected children will require treatment from a multidisciplinary team to address any associated physical, developmental, hearing, and visual and learning difficulties that may occur in association with the NTD.
  • The newborn with an open NTD should be kept warm and the defect covered with a sterile saline dressing.
  • The baby should be positioned in the prone position to prevent pressure on the defect.
  • Open NTDs should be closed promptly.
  • Hydrocephalus: ventriculoperitoneal shunt placed at the time of myelomeningocele closure.
  • Symptomatic Chiari malformations: suboccipital craniotomy and decompression of the posterior fossa and tonsils.
  • Syrinx (a fluid-filled cavity within the spinal cord or brainstem): laminectomy and placement of a syringosubarachnoid stent to divert the CSF out of the central canal.
  • In utero surgical repair has been practised in several centres in the USA for many years. [3] The Management of Myelomeningocele Study (MOMS) has now evaluated this in a controlled trial and shown short-term benefits for the newborn, including 50% reduction in the need for hydrocephalus shunting and significant improvement in spinal neurological function. [10]

Complications

  • Infections.
  • Associated motor and sensory problems, particularly lower-limb.
  • Associated general learning disability, developmental delay and hearing impairment.
  • Bladder and bowel dysfunction.

This depends on the nature of the defect and associated malformations.

Prevention

  • Periconceptional folate supplementation has a strong protective effect against NTDs. [11] Supplementation must begin before conception for it to be effective. [12]
  • To prevent a first occurrence, women who are planning to become pregnant should take 400 micrograms of folic acid daily before conception and during the first 12 weeks of pregnancy. [13] To prevent recurrence, 5 mg folic acid daily should be taken.
  • Food fortification with the addition of folate to grain products is considered the most effective method of ensuring adequate intake of folic acid in pregnant women. [14]

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Final Recommendation Statement

Folic Acid for the Prevention of Neural Tube Defects: Preventive Medication

Recommendations made by the USPSTF are independent of the U. S. government. They should not be construed as an official position of the Agency for Healthcare Research and Quality or the U. S. Department of Health and Human Services.

Recommendation Summary

The USPSTF recommends that all women who are planning or capable of pregnancy take a daily supplement containing 0.4 to 0.8 mg (400 to 800 µg) of folic acid.

To read the recommendation statement in JAMA, select here.

To read the evidence summary in JAMA, select here.

Table of Contents

The US Preventive Services Task Force (USPSTF) makes recommendations about the effectiveness of specific preventive care services for patients without obvious related signs or symptoms.

It bases its recommendations on the evidence of both the benefits and harms of the service and an assessment of the balance. The USPSTF does not consider the costs of providing a service in this assessment.

The USPSTF recognizes that clinical decisions involve more considerations than evidence alone. Clinicians should understand the evidence but individualize decision making to the specific patient or situation. Similarly, the USPSTF notes that policy and coverage decisions involve considerations in addition to the evidence of clinical benefits and harms.

Importance

Neural tube defects are major birth defects of the brain and spine that occur early in pregnancy due to improper closure of the embryonic neural tube, which may lead to a range of disabilities or death. The most common neural tube defects are anencephaly (an underdeveloped brain and an incomplete skull) and spina bifida (incomplete closing of the spinal cord). 1 , 2 Based on 2009–2011 data, the estimated average annual prevalence of anencephaly and spina bifida combined was 6.5 cases per 10,000 live births. 1-3 Daily folic acid supplementation in the periconceptional period can prevent neural tube defects. 1 , 2

Folic acid is the synthetic form of folate, a water-soluble B vitamin (B9). Folic acid is usually given as a multivitamin, prenatal vitamin, or single supplement. It is also used to fortify cereal grain products. Folate occurs naturally in foods such as dark green leafy vegetables, legumes, and oranges. 1 However, most women do not receive the recommended daily intake of folate from diet alone. 1 National Health and Nutrition Examination Survey (NHANES) data from 2003 to 2006 suggest that 75% of nonpregnant women aged 15 to 44 years do not consume the recommended daily intake of folic acid for preventing neural tube defects. 1 , 2 , 4

Recognition of Risk Status

Women who have a personal or family history of a pregnancy affected by a neural tube defect are at increased risk of having an affected pregnancy. However, most cases occur in the absence of any personal or family history.

Benefits of Preventive Medication

The USPSTF found convincing evidence that folic acid supplementation in the periconceptional period provides substantial benefits in reducing the risk of neural tube defects in the developing fetus. The USPSTF found inadequate evidence on how the benefits of folic acid supplementation may vary by dosage, timing relative to pregnancy, duration of therapy, or race/ethnicity.

Harms of Preventive Medication

The USPSTF found adequate evidence that the harms to the mother or infant from folic acid supplementation taken at the usual doses are no greater than small.

USPSTF Assessment

The USPSTF concludes with high certainty that the net benefit of daily folic acid supplementation to prevent neural tube defects in the developing fetus is substantial for women who are planning or capable of pregnancy.

Clinical Considerations

Patient Population Under Consideration

This recommendation applies to women who are planning or capable of pregnancy. It does not apply to women who have had a previous pregnancy affected by neural tube defects or who are at very high risk due to other factors (e. g., use of certain antiseizure medications or family history). These women may be advised to take higher doses of folic acid.

Assessment of Risk

Although all women of childbearing age are at risk of having a pregnancy affected by neural tube defects and should take folic acid supplementation, some factors increase their risk, including a personal or family history (first – or second-degree relative) of neural tube defects. 1 Women with a personal history of an affected pregnancy require special care and are not within the scope of this recommendation statement. Other risk factors include the use of particular antiseizure medications (e. g., valproic acid or carbamazepine), maternal diabetes, obesity, and mutations in folate-related enzymes. 1

Questions persist regarding increased risk of neural tube defects in some racial/ethnic groups. Birth prevalence rates are highest among Hispanic women, followed by non-Hispanic white and non-Hispanic black women. 1 Genetic mutations in folate-related enzymes may vary by race/ethnicity. Dietary folate or folic acid intake differs by race/ethnicity. For example, Mexican American women may be at increased risk because of decreased consumption of fortified foods and greater intake of corn masa–based diets. 1 Fewer Hispanic women (28%) report consuming 0.4 mg (400 µg) or more of folic acid daily through fortified food or supplements, compared with 39% of non-Hispanic white women. 1 , 5

Half of all pregnancies in the United States are unplanned. 6 Therefore, clinicians should advise all women who are capable of pregnancy to take daily folic acid supplements. The critical period for supplementation starts at least 1 month before conception and continues through the first 2 to 3 months of pregnancy. 1 , 7 , 8

Trials and observational studies conducted in settings without food fortification suggest that supplementation with a multivitamin containing 0.4 to 0.8 mg (400 to 800 µg) of folic acid decreases the risk of neural tube defects. 1 , 7 , 8 Evidence shows that most women in the United States are not consuming fortified foods in a quantity needed to demonstrate optimal benefit. 8 An analysis of NHANES data found that 48% of respondents of childbearing age consumed the recommended amount of folic acid from mandatorily fortified foods only. 1 , 9

According to the National Academy of Sciences Food and Nutrition Board, the tolerable upper intake level of folic acid in women 19 years and older is 1 mg/d (1000 µg/d) from supplements or fortified food (excluding naturally occurring folate) and 0.8 mg/d (800 µg/d) for those aged 14 to 18 years. 10 Fewer than 3% of girls and women aged 14 to 50 years receive more than 1 mg/d (1000 µg/d) of folic acid from supplements or food. 3 , 11 , 12

Additional Approaches to Prevention

The Community Preventive Services Task Force recommends community-wide education campaigns to encourage women of childbearing age to take folic acid supplements. 13

In 2016, the US Food and Drug Administration approved folic acid fortification of corn masa flour. This allows manufacturers to voluntarily add folic acid to corn masa flour at levels consistent with those found in other enriched cereal grains. 14

Other Considerations

Research Needs and Gaps

Study results on the effectiveness of folic acid supplementation in reducing neural tube defects among Hispanic women compared with white or black women have been inconsistent. Future research should continue to evaluate differences in diverse populations. 1

Discussion

Burden of Disease

During early fetal development, a neural tube forms that later becomes the spinal cord, brain, and neighboring protective structures (e. g., spinal column), with complete closure occurring by the fourth week of pregnancy. Incomplete neural tube closure results in defects such as anencephaly and spina bifida. These defects vary in level of disability and may lead to death. Neural tube defects are among the most common major congenital anomalies in the United States. 1 Based on 2009–2011 data from the Centers for Disease Control and Prevention, the estimated average annual prevalence of anencephaly and spina bifida combined was 6.5 cases per 10,000 live births. 1 , 2

Since widespread recommendations on folic acid supplementation and the implementation of food fortification laws by the US Food and Drug Administration in 1998, prevalence rates of infants born with neural tube defects have decreased. 1 , 2 Prevalence of neural tube defects declined from 10.7 cases per 10,000 live births before the implementation of food fortification (1995 to 1996) to 7.0 cases per 10,000 live births after fortification (1999 to 2011). 2 Folic acid supplementation prevents about 1300 annual births from being affected by neural tube defects, according to recent estimates. 2 Although supplementation recommendations and food fortification laws have reduced the prevalence of neural tube defects, it is still difficult for most women to consume the daily requirement of 0.4 mg (400 μg) of folic acid from food alone. The 2007–2012 NHANES found that 48% of respondents of childbearing age reported consuming folic acid from mandatorily fortified foods only. Only 29% of all respondents reported taking a daily folic acid supplement. 9 Among women who were taking a daily folic acid supplement, about half (14.6% of all women) were taking a supplement containing less than the daily recommended dose of 0.4 mg (400 µg). 1 , 9

Scope of Review

In 2009, the USPSTF reviewed the effectiveness of folic acid supplementation in women of childbearing age for the prevention of neural tube defects in infants. 7 The current review assessed new evidence on the benefits and harms of folic acid supplementation. The USPSTF did not review the evidence on folic acid supplementation in women with a history of pregnancy affected by neural tube defects or other high-risk factors. Evidence on folic acid fortification, counseling to increase dietary intake of folic acid or naturally occurring food folate, or screening for neural tube defects is also outside the scope of this review.

Effectiveness of Preventive Medication

In 2009, the USPSTF reviewed the evidence on folic acid supplementation in women of childbearing age and found that the benefits are well-established and outweigh the harms. 8

In the current review, the USPSTF evaluated 1 randomized clinical trial (RCT), 2 cohort studies, 8 case-control studies, and 2 publications from the previous USPSTF review for evidence of effectiveness of folic acid supplementation (n = at least 41,802 participants). Results were not pooled because of study heterogeneity and differences in food fortification over time.

A fair-quality RCT conducted in Hungary (1984–1992) assessed women (n = 5453) without a personal history of pregnancy affected by neural tube defects. 1 , 15 Participants were randomized to receive either a daily vitamin supplement containing 0.8 mg (800 μg) of folic acid (experimental group) or a daily trace-element supplement (control group) in the periconceptional period. The trial reported no cases of neural tube defects in the experimental group and 6 cases in the control group (0% vs 0.25%; P = 0.014 by Fisher exact test). 15 These results indicate a statistically significant lower odds of neural tube defects with folic acid supplementation (Peto odds ratio [OR], 0.131 [95% CI, 0.0263 to 0.648]; P = 0.013). 1 , 15

Evidence from older, fair-quality observational studies provide additional support that folic acid supplementation is beneficial. 1 , 5 A fair-quality prospective cohort study (n = 6112) conducted in Hungary compared women who were provided a vitamin supplement containing 0.8 mg (800 μg) of folic acid before conception with unsupplemented women at the first prenatal visit (between 8 and 12 weeks of pregnancy) and showed a statistically significant effect on the odds of neural tube defects (OR, 0.11 [95% CI, 0.01 to 0.91]). 1 , 16 . A fair-quality retrospective cohort study conducted in the United States in women undergoing ɑ-fetoprotein testing or amniocentesis between 15 and 20 weeks of pregnancy showed a statistically significant effect on the odds of neural tube defects among 10,713 women who took multivitamins containing folic acid in weeks 1 through 6 of pregnancy compared with 3157 women who did not take any supplements (OR, 0.27 [95% CI, 0.11 to 0.63]). 1 , 17

The 8 remaining studies were fair-quality case-control studies of births occurring over 3 decades, from 1976 through 2008. 1 Studies compared infants who had malformations caused by neural tube defects to either nonmalformed infants or infants who had malformations not caused by neural tube defects. Data were drawn from 2 multistate studies (National Birth Defects Prevention Study and the Slone Epidemiology Center Birth Defects Study), a 2-state study (National Institute of Child Health and Human Development Neural Tube Defects Study), and 2 single-state studies (Texas Neural Tube Defect Project and the California Birth Defects Monitoring Program). 1 Older case-control studies conducted before implementation of food fortification laws were generally consistent with the more recent evidence showing that folic acid supplementation is beneficial for the prevention of neural tube defects (OR range, 0.6 to 0.7 [in 3 of 4 studies]). Newer case-control studies conducted after food fortification did not show a protective effect of folic acid supplementation on neural tube defects (OR range, 0.93 to 1.40 [95% CI included the null]). 1

Ethical considerations limited the use of RCT methods to study the effects of folic acid supplementation after food fortification. The newer studies are more subject to design issues than the older ones, which had fewer design flaws. 1 Case-control studies have the potential for selection and recall bias, both of which can reduce the observed effect of folic acid supplementation on neural tube defects. Another issue with all study designs is the relative rarity of the outcome and the challenge of adequately powering studies to determine benefits. Another potential explanation for the findings is that the majority of cases of neural tube defects due to folate deficiency have now been prevented, and subsequent cases result from a different etiology. Despite this possible rationale, evidence indicates that most women are not consuming fortified foods at the level needed for optimal benefit. Inadequate folate intake continues to leave nearly one-fourth of the US population with suboptimal red blood cell folate concentration. 1 , 9

Three fair-quality case-control studies (n = 11,154) examined the effects of folic acid supplementation by race/ethnicity. 1 , 18-20 One study found that folic acid supplementation may be less protective among Hispanic women compared with white or black women. 18 A second study found a statistically nonsignificant increased risk of neural tube defects with supplementation among Hispanic women (OR adjusted for consistent users vs nonusers, 2.20 [95% CI, 0.98 to 4.92]). 19 . A third study found that periconceptional supplementation did not decrease the risk of neural tube defects and reported no differences in effect by race/ethnicity. 20 These inconsistent results among Hispanic women could be a result of chance due to small sample sizes.

Eight fair-quality case-control studies addressed dose, timing, or duration of therapy. 1 Of these 8 studies, 4 (n = 26,791) provided information on dose, 5 (n = 26,808) provided information on timing, and none provided information on duration. Across the studies, evidence was inconsistent that the benefits of folic acid supplementation differ by dosage or timing. 1

Potential Harms of Preventive Medication

The USPSTF found adequate evidence that folic acid supplementation does not have serious harms. One fair-quality trial and 1 fair-quality cohort study did not find evidence of a statistically significant increased risk of pregnancy with twins in women. 1

In the Hungarian trial (n = 5453), the rate of twin pregnancy was not statistically significantly different between the multivitamin and trace-element groups (OR, 1.4 [95% CI, 0.97 to 2.25]). 1 , 21 In a retrospective, population-based cohort study in Norway (n = 176,042), no association was found between folic acid supplementation and twin pregnancy (OR, 1.04 [95% CI, 0.89 to 2.21]) after adjusting for use of in vitro fertilization, maternal age, and parity. 22

The Hungarian trial examined adverse events in women and found a potential increased risk of maternal weight gain, diarrhea, and constipation at 12 weeks of pregnancy. However, there was a low event rate, and these symptoms could have occurred by chance. These symptoms are also associated with pregnancy. 1 , 15

Three systematic reviews of observational studies (n = at least 14,438 participants) evaluated childhood asthma, wheezing, or allergies and found inconsistent evidence of harms. 1 , 23 , 24 Evidence was also inconsistent on the harms of folic acid supplementation differing by dosage and timing. No evidence was found on harms differing by duration of therapy. 1 .

Other potential hypothesized harms of folic acid supplementation include the masking of symptoms of vitamin B12 deficiency and subsequent neurologic complications, carcinogenic effects, asthma/allergic reactions, and interactions with medications. 1 , 7 , 10 The USPSTF found no significant evidence of these potential harms.

Estimate of Magnitude of Net Benefit

The USPSTF found no new substantial evidence on the benefits and harms of folic acid supplementation that would lead to a change in its recommendation from 2009. 7 The USPSTF assessed the balance of the benefits and harms of folic acid supplementation in women of childbearing age and determined that the net benefit is substantial. Evidence is adequate that the harms to the mother or infant from folic acid supplementation taken at the usual doses are no greater than small. Therefore, the USPSTF reaffirms its 2009 recommendation that all women who are planning or capable of pregnancy take a daily supplement containing 0.4 to 0.8 mg (400 to 800 µg) of folic acid. 8

How Does Evidence Fit With Biological Understanding?

Genetic predisposition and environmental influences are thought to contribute to neural tube defects. These environmental influences are being investigated. An important environmental influence is the consumption of folate. The mechanism of action of folate in the prevention of neural tube defects is unknown. Folate acts as a coenzyme in the synthesis of nucleic acids and the metabolism of amino acids. An important function of folate is its role in single-carbon transfers, which are important in methylation reactions and in purine and pyrimidine synthesis. Folate is necessary for the regulation of DNA synthesis and function; reduced concentrations of folate may limit the number of methyl groups available for DNA replication and methylation. 1 , 7 , 10

Evidence suggests that mutation in the MTHFR gene, which encodes the enzyme methylenetetrahydrofolate reductase, is a risk factor for neural tube defects. This enzyme regulates folate and homocysteine levels. Persons who have this gene mutation have decreased folate levels, which reduces the conversion of homocysteine to methionine and may increase the risk of neural tube defects. 1 , 25 Folic acid consumption may help diminish the effects of the gene mutation.

Response to Public Comment

A draft version of this recommendation statement was posted for public comment on the USPSTF website from May 10 to June 6, 2016. Some comments requested a more detailed definition of “excessive” folic acid. In response, the USPSTF added information about tolerable upper intake levels for folic acid. Other comments suggested emphasizing that many women do not meet daily recommended amounts of folic acid and adding language on the potential harms of folic acid supplementation. The USPSTF added language about the harms of supplementation and the difficulty of consuming enough folic acid from food alone.

Update of Previous USPSTF Recommendation

This recommendation reaffirms the 2009 recommendation statement on folic acid supplementation in women of childbearing age. 8 The current statement recommends that all women who are planning or capable of pregnancy take a daily supplement containing 0.4 to 0.8 mg (400 to 800 µg) of folic acid.

Recommendations of Others

The Health and Medicine Division of the National Academies (formerly the Institute of Medicine), American College of Obstetricians and Gynecologists, American Academy of Family Physicians, US Public Health Service, Centers for Disease Control and Prevention, American Academy of Pediatrics, American Academy of Neurology, and American College of Medical Genetics and Genomics recommend that women who are capable of becoming pregnant should take at least 0.4 mg (400 µg) of folic acid daily. 10 , 26-30 The American College of Obstetricians and Gynecologists, Centers for Disease Control and Prevention, and several other organizations recommend that women with a history of neural tube defects or other high-risk factors take 4 mg (4000 μg) of folic acid daily. 31-33

Members of the U. S. Preventive Services Task Force

The US Preventive Services Task Force (USPSTF) members include the following individuals: Kirsten Bibbins-Domingo, PhD, MD, MAS (University of California, San Francisco); David C. Grossman, MD, MPH (Group Health Research Institute, Seattle, Washington); Susan J. Curry, PhD (University of Iowa, Iowa City); Karina W. Davidson, PhD, MASc (Columbia University, New York, New York); John W. Epling Jr, MD, MSEd (State University of New York Upstate Medical University, Syracuse); Francisco A. R. García, MD, MPH (Pima County Department of Health, Tucson, Arizona); Alex R. Kemper, MD, MPH, MS (Duke University, Durham, North Carolina); Alex H. Krist, MD, MPH (Fairfax Family Practice Residency, Fairfax, Virginia, and Virginia Commonwealth University, Richmond); Ann E. Kurth, PhD, RN, MSN, MPH (Yale University, New Haven, Connecticut); C. Seth Landefeld, MD (University of Alabama at Birmingham); Carol M. Mangione, MD, MSPH (University of California, Los Angeles); William R. Phillips, MD, MPH (University of Washington, Seattle); Maureen G. Phipps, MD, MPH (Brown University, Providence, Rhode Island); Michael P. Pignone, MD, MPH (University of Texas at Austin); Michael Silverstein, MD, MPH (Boston University, Boston, Massachusetts); Chien-Wen Tseng, MD, MPH, MSEE (University of Hawaii, Manoa).

Copyright and Source Information

Source: This article first appeared in JAMA on January 10, 2017.

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Authors followed the policy regarding conflicts of interest described at https://www. uspreventiveservicestaskforce. org/Page/Name/conflict-of-interest-disclosures. All members of the USPSTF receive travel reimbursement and an honorarium for participating in USPSTF meetings.

Funding/Support: The USPSTF is an independent, voluntary body. The US Congress mandates that the Agency for Healthcare Research and Quality (AHRQ) support the operations of the USPSTF.

Disclaimer: Recommendations made by the USPSTF are independent of the US government. They should not be construed as an official position of AHRQ or the US Department of Health and Human Services.

Copyright Notice: USPSTF recommendations are based on a rigorous review of existing peer-reviewed evidence and are intended to help primary care clinicians and patients decide together whether a preventive service is right for a patient’s needs. To encourage widespread discussion, consideration, adoption, and implementation of USPSTF recommendations, AHRQ permits members of the public to reproduce, redistribute, publicly display, and incorporate USPSTF work into other materials provided that it is reproduced without any changes to the work of portions thereof, except as permitted as fair use under the US Copyright Act.

AHRQ and the US Department of Health and Human Services cannot endorse, or appear to endorse, derivative or excerpted materials, and they cannot be held liable for the content or use of adapted products that are incorporated on other Web sites. Any adaptations of these electronic documents and resources must include a disclaimer to this effect. Advertising or implied endorsement for any commercial products or services is strictly prohibited.

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