Neural Tube Defects Screening
WHEC Practice Bulletin and Clinical Management Guidelines for healthcare providers. Educational grant provided by Women's Health and Education Center (WHEC).
Neural tube defects (NTDs) are congenital structural abnormalities of the brain and vertebral column that occur either as an isolated malformation, along with other malformations, or as a part of genetic syndrome. Isolated (i.e., non-syndromic) NTDs occur in 1.4-2 per 1,000 pregnancies and are the second most common major congenital anomaly worldwide (cardiac malformations are first). In the United States, approximately 4,000 fetuses are affected each year, of which one third are either aborted or spontaneously lost (1). The prevalence of congenital anomalies of the central nervous system (CNS) varies in different epidemiologic studies, mostly as a consequence of the type of ascertainment and the length of follow up. Ethnic and geographic factors play a role as well. Long-term follow-up studies in the United States and Europe suggest an incidence of about 1 in 100 births. High frequencies of these anomalies are ascertained in spontaneous abortions, suggesting an elevated intrauterine fatality rate. The CNS was probably the first organ to be investigated in utero by diagnostic ultrasound. Anencephaly was the first congenital anomaly to be recognized by this technique before viability. Since then, the investigation of the fetal neural axis has steadily remained a central issue of antenatal sonography.
The purpose of this document is to review prenatal screening, diagnosis that are widely available and prenatal therapy is being investigated. Neural tube defects (NTDs) are among the few birth defects for which primary prevention is possible. Yet identification of selected anomalies, such as ventriculomegaly and spina bifida, remains a challenge in many cases. Anencephaly accounts for one half of all cases of NTDs and is incompatible with life; with treatment, 80-90% of infants with spina bifida survive with varying degrees of disability (2). In this chapter, the sonographic investigation, screening for NTDs and role of folic acid are also reviewed.
The fetal cerebrum undergoes major developmental changes throughout gestation. Fetal ultrasonography demands a thorough knowledge of the ontogeny of the brain. The neural plate appears during the third week of gestation and gives rise to the neural folds that fuse in the midline to form the neural tube. NTDs result either from failure of closure of one site or failure of two sites to meet. Neural tube closure is normally complete by the end of the fourth week after conception (6 weeks after the last period), a time when many women do not yet realize they are pregnant. Before the 13th week of gestation, the choroid plexus normally fills the lateral ventricle, almost in its entirety. At approximately 13 to 15 weeks gestation, as the choroid plexus assumes its more normal posterior location; the anterior horns of the lateral ventricles appear quite prominent. This normal development and the prominence of the anterior horns of the lateral ventricles, now devoid of choroid plexus, may simulate ventriculomegaly of one is not aware of this development process (3). Likewise, the corpus callosum first begins to develop at 12 weeks of gestation but is not complete until 18 to 20 weeks of gestation. At 18 to 20 weeks of gestation, the cavum septum pellucidum and the course of the pericallosal artery can be demonstrated sonographically, confirming the presence of corpus callosum. Scans obtained before this time might wrongly suggest the diagnosis of agenesis of the corpus callosum. Last, before 18 to 22 weeks gestation, the normal and more recognizable posterior fossa relationships of the fourth ventricle, cistern magna, cerebellar vermis, and cerebellar hemisphere are not present.
Categorization of Neural Tube Defects (NTDs):
Neural tube defects can be categorized as either cranial or spinal defects (4). Cranial defects include abnormalities in skull, scalp, and brain tissue formation. These conditions, with the exception of encephaloceles, are lethal.
Abnormalities of the caudal portion of the neural tube generally are known as spina bifida. The various types of spina bifida include malformations of the spinal cord, meninges, and vertebrae, and most of these conditions are compatible with life.
Anencephaly -- failure of fusion of cephalic portion of neural folds; absence of all or part of brain, neurocranium, and skin.
Exencephaly -- failure of scalp and skull formation; exteriorization of abnormally formed brain.
Encephalocele -- failure of skull formation; extrusion of brain tissue into membranous sac.
Iniencephaly -- defect of cervical and upper thoracic vertebrae; abnormally formed brain tissue and extreme retroflexion of upper spine.
Spina bifida -- failure of fusion of caudal portion of neural tube, usually of 3-5 contiguous vertebrae; spinal cord or meninges or both exposed to amniotic fluid.
Meningocele -- failure of fusion of caudal portion of neural tube, usually of 3-5 contiguous vertebrae; spinal cord or meninges or both exposed to amniotic fluid.
Meningomyelocele -- failure of fusion of caudal portion of neural tube; meninges and neural tissue exposed.
Myeloschisis -- failure of fusion of caudal portion of neural tube; flattened mass of neural tissue exposed.
Holorachischisis -- failure of fusion of vertebral arches; entire spinal cord exposed.
Craniorachischisis -- co-existing anencephaly and rachischisis.
Isolated (non-syndromic) NTDs are believed to be the result of a combination of genetic predisposition and environmental influences. Genetic predisposition is illustrated by the fact that NTDs tend to occur more frequently in certain families, and parents who have had one child with an NTD are at significantly increased risk of having another child with the same or similar defect. However, only 5% of NTDs occur in families with a positive family history (5). More than 90% occur in families with no prior history, possibly because genetically susceptible individuals had not been exposed to the environmental influences necessary to produce a defect in their offspring. Any environmental influence must be present during the first 28 days of gestation, when neural tube is forming, to produce a defect. Factors known to be associated with NTDs include geographic region, ethnicity, diet, teratogen exposure, maternal diabetes, and high maternal core temperature. Regions with the highest NTD incidence include the British Isles, China, Egypt, and India. Most isolated NTDs occur in association with abnormal folate metabolism. Genetic syndromes that can include an NTD and are likely to have a genetic etiology other than abnormal folate metabolism include Meckel-Gruber, Roberts, Jarcho-Levin, and HARD syndromes, as well as trisomy 13, trisomy 18, and triploidy.
Risk factors for fetal neural tube defects:
Maternal Predisposing Factors: previous infant with a neural tube defect; first-degree relative with a neural tube defect; maternal serum AFP level greater than the laboratory cut-off with confirmed dates; suspicious screening ultrasound; maternal pre-existing diabetes; maternal obesity (6).
Multifactorial inheritance: anencephaly, myelomeningocele, meningocele, encephalocele.
Single Mutant Genes: Meckel's syndrome, autosomal recessive (phenotype includes occipital encephalocele and rarely anencephaly); median cleft facial syndrome, possibly autosomal dominant (phenotype includes anterior encephalocele); Roberts syndrome, autosomal recessive (phenotype includes anterior encephalocele); syndrome of anterior sacral myelomeningocele and anal stenosis, dominant (either autosomal or X linked); Jarcho-Levin syndrome, autosomal recessive (phenotype includes myelomeningocele); HARD syndrome, autosomal recessive (phenotype includes encephalocele).
Chromosome Abnormalities: trisomy 13, trisomy 18, triploidy, other abnormalities such as unbalanced translocation and ring chromosome.
Probably Hereditary But Mode of Transmission Not Established: syndrome of occipital encephalocele, myopia, and retinal dysplasia; anterior encephalocele among Bantus and Thais.
Teratogens: maternal peri-conceptional use of valproic acid or Depakote (phenotype includes spina bifida; amniopterin / methotrexate (phenotype includes anencephaly and encephalocele); thalidomide (phenotype includes rarely anencephaly and myelomeningocele).
Specific Phenotypes But Without Known Cause: syndrome of craniofacial and limb defects secondary to aberrant tissue brands (phenotype includes multiple encephaloceles) cloacal exstrophy (phenotype include myelocystocele); sacrococcygeal teratoma (phenotype includes myelomeningocele).
Clinical Consequences of NTDs:
The increase intracranial pressure caused by ventriculomegaly usually is relieved by placement of a ventricular-peritoneal shunt. Most infants with spina bifida and ventriculomegaly require shunting in their first year, and at least two thirds require several non-elective shunt revisions over the course of their lifetime. Worsening of the Arnold-Chiari malformation, due in part to the small size of the posterior fossa, can cause severe or even lethal neurologic dysfunction, leading to respiratory and swallowing abnormalities. Surgical compression of the posterior fossa involves significant risk. With aggressive therapy at birth, including surgical closure of the defect within the first 48 hours of life, the degree of motor and sensory handicap associated with spina bifida is predicted most accurately by the level of the lesion: the higher the lesion, the worse the prognosis. Most individuals with thoracic lesions are wheelchair-bound, while 90% of those with sacral lesions can ambulate. Most individuals with spina bifida, even those with low lesions, have some impairment of bowel and bladder function; urinary tract infections and stones are a common cause of chronic morbidity and even mortality caused by sepsis or renal failure (7). Sexual function may be affected by lack of genital sensation and difficulty achieving erection and ejaculation. Endocrine abnormalities, tethered cord, kyphosis, syringomyelia, and syringobulbia may develop as a result of neurologic defect or repair. At least one third of individuals with an NTD has a severe allergy to latex and can have life-threatening reactions after exposure. Although most children with spina bifida have a normal intelligent quotient, intelligence may be affected. A reduction in mental functioning may occur as a result of central nervous system infection or increased intracranial pressure caused by shunt malfunction. Intellectual decline also may be associated with intraoperative complications during repair of an Arnold-Chiari malformation or another neurosurgical procedure.
In 1985, the American College of Obstetricians and Gynecologists (ACOG) produced an alert from the Professional Liability Committee which recommended that all women be offered; maternal serum alpha-fetoprotein (MSAFP) screening to increase the prenatal detection of open neural tube defects. MSAFP is offered between 15 to 22 weeks of pregnancy. Alpha-fetoprotein (AFP) is a protein, produced originally in the yolk sac and then primarily in the fetal liver. The concentration in the fetal serum is approximately 40,000-50,000 times that in the maternal serum. The fetus excretes AFP in urine. It enters the maternal serum most likely by transport across the placenta and membranes. By performing population studies of the level of MSAFP in normal singleton, well-dated pregnancies, it was possible to develop a standard curve of how much AFP is normal in the maternal serum at different gestational ages. In situations in which there is an elevated production of AFP (such as in multiple gestations), increased excretion of AFP in the amniotic cavity (fetal nephritic syndrome) or loss of fetal skin integrity such that the fetal intravascular AFP can "leak" into the amniotic fluid at higher levels (open neural tube defects, ventral wall defects, fetal dermatologic disorders), then the MSAFP levels are likely to be higher than normal. Fetal to maternal hemorrhage, such as in cases with early placental dysfunction, can also increase the MSAFP. This is likely the source of the association of elevated MSAFP levels with increase rates of growth restriction, preterm birth, and maternal preeclampsia (8).
As with any screening program, a decision has to be made about the balance of the sensitivity and specificity of the test. Historically, MSAFP levels ≥2.50 multiples of the median (MoM) had been associated with a detection rate of 88% of patients with anencephaly and 79% of those with spina bifida, for testing performed at 16-18 weeks' gestation. Typically, the cut-off value for prenatal screening is set so that the detection rate will be approximately 80% and 5% of the population will be considered to have an abnormal test. Increasing the detection rate significantly results in many more women being identified falsely and put through the anxiety-provoking and expensive process of the evaluation of an abnormal MSAFP. However, in the 20 plus years since MSAFP screening was recommended by ACOG for the general population, significant changes in the use of ultrasound and better understanding of the factors that place a woman at increased risk of bearing a child with spina bifida (and thus a candidate for diagnostic testing and not screening) have changed the utility of MSAFP screening. This screening is commonly performed in conjunction with measurement of other analyses to provide Down syndrome risk assessment. As prenatal screening for Down syndrome with nuchal translucency and first trimester analyses is carried out more commonly, it is likely that fewer women will then also choose to undergo second trimester screening with MSAFP. However, that remains to be determined. The routine ultrasound compares favorably with MSAFP screening in the primary identification of neural tube defects (9).
Perinatal and functional outcomes of NTDs:
Natural history studies correlating prenatal findings with postnatal outcomes are very difficult to perform. Part of this relates to pregnancy termination in identified issues. Although there are wide regional variations, in the USA as many as 20-30% of fetuses with spina bifida are electively terminated. In addition, there is a wide spectrum of outcomes with spina bifida. Attempting to predict cognitive function, motor abilities, lifespan, and quality-of-life has to be undertaken with some trepidation. Nonetheless, several authors have studied prenatal findings and correlated them with postnatal outcomes in order to provide some guidance in this area. The degree of fetal ventriculomegaly considerably influences the postnatal intellectual performance regardless of the motor status. There is, however, no cut-off for the measurements of the ventricular enlargement below which normal intellectual development could be assured. There is estimated 13% overall mortality rate predominantly related to complications of surgery or hind brain herniation. In general, higher the spinal lesion the more likely it is for the fetus to develop large ventricles. It seems clear that the lower the lesion level, the better the prognosis. In addition, the absence of ventriculomegaly at the initial diagnosis suggests a smaller ventricular size at birth than in those with ventriculomegaly at the time of initial diagnosis (10). However, none of these findings accurately predict with a high degree of certainty what the outcome will be for the individual fetus being evaluated. Substantial work is to be done for families who have to consider their options and for patient selection if maternal-fetal surgery for spina bifida proves to be efficacious.
Role of folic acid in prevention of NTDs:
The most important environmental influence on NTD formation appears to be diet or, more specifically, the intake of folic acid. It has long been known that women with pregnancies complicated by fetal NTDs have lower plasma levels of vitamin B12 and folate than women whose pregnancies are unaffected. Many of the medications known to cause fetal NTDs, such as diphenylhydantoin, aminopterin, or carbamazepine, interfere with folic acid metabolism. The genetic basis for the relationship between folate metabolism and NTDs is now being investigated. The most important metabolic reaction that requires folate is the conversion of homocysteine to methionine; evidence indicates that this pathway is critically involved in the genesis of NTDs. Several studies have shown that parents who have had a pregnancy complicated by an NTD and their affected offspring are more likely to carry a mutation in the gene coding the enzyme methylenetetra-hydrofolate reductase (MTHFR) than the unaffected population. Other mutations in this enzyme with similar effects also have been reported. Therefore, it seems possible that folic acid supplementation helps to overcome the effects of this enzyme mutation, resulting in more normal levels of homocysteine and adequate production of methionine (11). Methionine is important because it provides the methyl group necessary for gene regulation and for a wide variety of metabolic reactions essential for tissue growth and development.
There is limited evidence to indicate that folic acid supplementation may not decrease the risk of NTDs in women with high first-trimester blood sugar levels, or high first-trimester maternal temperature, or in women who take valproic acid. In women with high glucose levels, the exact mechanism is unknown but may involve inhibition of fetal glycolysis, a functional deficiency of arachidonic acid or myoinositol in the developing embryo, or alterations in the yolk sac (12). First-trimester maternal fever and sauna use both increases the relative risk of NTDs, although the duration and intensity necessary to produce an effect and the embryologic mechanism are unknown. First-trimester valproic acid use results in a 1-2% risk of having a fetus with spina bifida, but the mechanism may be different from that of other antiepileptic agents. Fetuses with aneuploidy or genetic syndromes may have NTDs as a result of their specific genetic abnormality. These NTDs are not prevented by folic acid.
Folic Acid Supplementation Recommendations:
In 1991, the Centers for Disease Control and Prevention recommended that all women with a previous pregnancy complicated by a fetal NTD ingest 4 mg of folic acid daily before conception and through the first trimester. The following year, the U.S. Public Health Service recommended that all women capable of becoming pregnant take 400 micro g of folic acid daily. Although grain fortification has improved the folate intake of all Americans, many authorities feel the current level of fortification is inadequate to prevent NTDs. It is currently recommended that women of reproductive age take a 400 micro g folic acid supplement daily. Calculations based on existing data predict that the 400 micro g dose recommended for women at low risk would reduce the incidence of NTDs by 36%. In this same analysis, the 4 mg dose, currently recommended only for women at high risk, was predicted to reduce the incidence by 82%, and a 5 mg dose was predicted to reduce the incidence by 85% (13). The risks of higher levels of folic acid supplementation are believed to be minimal. Folic acid is considered non-toxic even at very high doses and is rapidly excreted in the urine. There have been concerns that supplemental folic acid could mask the symptoms of pernicious anemia and thus delay treatment. However, folic acid cannot mask the neuropathy typical of this diagnosis. Currently, 12% of patients with pernicious anemia present with neuropathy alone. With folic acid supplementation, this proportion may be increased, but there is no evidence that initiating treatment after the development of a neuropathy results in irreversible damage. Women taking seizure medication (diphenylhydantoin, amniopterin, carbamazepine) may have lower serum drug levels and experience an associated increase in seizure frequency while taking folic acid supplements. Monitoring drug levels and increasing the dosage as needed may help to avert this complication.
Some over-the-counter multivitamin supplements and most prenatal vitamins contain 400 micro g of folic acid. Higher levels of supplementation should be achieved by taking an additional folic acid supplement and not by taking excess multivitamins. In particular, vitamin A is potentially teratogenic at high doses, and pregnant women should not take more than the 5,000 IU per day, which is typically found in on multivitamin / mineral supplement.
Special considerations in the obstetric management and route of delivery:
Fetal spina bifida does not increase the risk of uteroplacental insufficiency or oligohydramnios; anencephaly can be associated with hydramnios as a result of decreased fetal swallowing. Serial ultrasound examinations to monitor fetal growth and ventricular size may be helpful in planning delivery. The fetus with spina bifida should be delivered at a hospital with neonatal intensive care facilities and personnel capable of managing the spine defect and any immediate complications; evidence suggests that outcomes are better in such settings. Because individuals with an NTD are at risk of developing a severe, potentially life-threatening allergy to latex, clinicians handling the infant should wear latex-free gloves. Generally, delivery at term is preferred. However, once fetal lung maturity has been documented, rapidly increasing ventriculomegaly may prompt delivery before term so that a ventriculo-peritoneal shunt can be placed. Breech presentation, resulting from fetal neurologic dysfunction or hydrocephalus with an enlarged head, is common in pregnancies complicated by fetal spinal bifida. For the breech fetus with an NTD, cesarean delivery is standard. The best delivery route for the vertex fetus remains controversial (14). Because it is still not clear whether or how the method of delivery significantly affects neurologic outcome in these infants, decisions about the timing and route of delivery should be made individually in consultation with personnel with experience and knowledge of complication, which may include maternal-fetal medicine specialists, neonatologists, and pediatric neurosurgeons.
Periconceptional folic acid supplementation is recommended because it has been shown to reduce the occurrence and recurrence of NTDs. For low-risk women, folic acid supplementation of 400 micro g per day currently is recommended because nutritional sources alone are insufficient. Higher levels of supplementation should not be achieved by taking excess multivitamins because of risk of vitamin A toxicity. For women at high-risk of NTDs or who have had a previous pregnancy with an NTD, folic acid supplementation of 4 mg per day is recommended. Maternal serum alpha-fetoprotein (MSAFP) evaluation is an effective screening test for NTD and should be offered to all pregnant women. Women with elevated AFP levels should have a specialized ultrasound examination to further assess the risk of NTDs. The fetus with an NTD should be delivered at a facility that has personnel capable of handling all aspects of neonatal complications. The route of delivery for the fetus with an NTD should be individualized because data are lacking that any one route provides a superior outcome.
Neural tube defects (NTDs) are a group of central nervous system disorders that result from the failure of normal primary neurulation, an embryologic process that is normally completed in the human by about day 26-28 post-conception. Among the neural defects, open spina bifida is of greatest public health interest, as this disorder is compatible with a near normal lifespan and varying degrees of impairment (both physical and cognitive). In addition, there is growing interest in whether its complications can be ameliorated with prenatal intervention. Thus, the pressure for early and accurate diagnosis is growing, in order to allow women reproductive options including pregnancy termination, selection of healthcare providers and hospitals in order to maximize neonatal well-being, and potential inclusion in the ongoing National Institute of Child Health and Human Development (NICHD) sponsored Management of Myelomeningocele Study (MOMS) of prenatal surgery for open spina bifida. Increasingly, efforts are being made to more accurately predict the likely outcome for the child with a particular lesion to facilitate informed decision making by the parent(s).
- World Health Organization
Prevention of Neural Tube Defects (pdf)
Area of work: nutrition (pdf)
- National Institutes of Health
Neural Tube Defects
- Centers for Disease Control and Prevention
Medical Progress in the Prevention of Neural Tube Defects
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- Dashe JS, Twickler DM, Santos-Ramos R et al. Alpha-fetoprotein detection of neural tube defects and the impact of standard ultrasound. Am J Obstet Gynecol epub, January 2008
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- Wald NJ, Law MR, Morris JK et al. Quantifying the effect of folic acid. Lancet 2001;358:2069-2073. (Level III)
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