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Understanding How Neural Tube Defects Occur--And Can Be Prevented Logo-CME

Author: Katharine D. Wenstrom, MD, University of Alabama

Back Abstract: Neural tube defects occur in 1.3 to 2.0 fetuses per 1000 live births, and are second only to cardiac malformations as the most frequent congenital anomaly in the US. The genetic and environmental influences on neural tube defect formation are currently being investigated. It is now thought that neural tube closure occurs in 5 separate sites, with each site possibly controlled by separate genes and subject to different external influences. Evidence suggests that one basic genetic defect involves homocysteine metabolism. Folic acid supplements before conception reduce both occurrence and recurrence risks. Prenatal screening and diagnosis are available, although management options after diagnosis are limited. Dietary alterations and adjustment of medical therapy prior to conception will reduce neural tube defect occurrence. [Medscape Women's Health 1(12), 1996. © 1996 Medscape, Inc.]

Key words: Neural tube defects * Folic acid * Homocysteine metabolism

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Contents

Back Introduction

Neural tube defects, or NTDs (anencephaly and spina bifida), are congenital structural abnormalities of the brain, skull, and spinal cord. They arise during the first 28 days of gestation, when the neural tube is forming. NTDs can occur as an isolated malformation or as part of a genetic syndrome or constellation of abnormalities. Isolated (nonsyndromic) NTDs occur in 1.3 to 2.0 fetuses per 1000 live births; after prenatal diagnosis and pregnancy termination, live birth rate is 0.6/1000.[1] The incidence of NTDs is second only to cardiac malformations as the most frequent congenital anomaly in the US. They are a major cause of stillbirth, neonatal and infant death, and lifelong severe handicap.

The most severe NTD is anencephaly, in which the forebrain, meninges, vault of the skull, and scalp all fail to form. This abnormality is incompatible with life, universally resulting in stillbirth or early neonatal demise. Other defects of the cranium include exencephaly (failure of scalp and skull formation with exteriorization of an abnormally formed brain); encephalocele (extrusion of brain tissue through a defect in the skull); and iniencephaly (a defect of the cervical and upper thoracic vertebrae and base of the skull with abnormally formed brain tissue and extreme retroflexion of the upper spine).

Spina bifida involves a failure of fusion of the vertebral arches so that meninges (meningocele) or neural tissue plus meninges (meningomyelocele) are exposed to the amniotic fluid and eventually to the environment. The neural tissue is damaged by such exposure, causing the structures supplied by the damaged nerves to be nonfunctional. Lesions in the lumbosacral area may lead to paraplegia and lack of bowel or bladder control. Higher lesions affect more structures and functions, and thus may result in even greater handicap. Open spine defects are often associated with ventriculomegaly (enlargement of the cerebral ventricles as a result of a block to cerebrospinal fluid circulation) or hydrocephalus (enlargement of the fetal cranium secondary to ventriculomegaly). The increased intracranial pressure caused by ventricular enlargement may cause permanent damage to the developing brain. With treatment, 80% to 90% of infants with spina bifida survive with varying degrees of handicap. Factors that influence eventual neurological function include the size and location of the defect, trauma to exposed neural tissue, timing of surgical closure, degree of associated ventriculomegaly, and occurrence of infection and other complications. The term rachischisis is used to describe the situation in which none of the vertebral arches fuse and the entire spine is open. This condition is generally incompatible with life.

Back Normal Neural Tube Closing in an Embryo

The neural plate appears during the third week of gestation, and then gives rise to the neural folds that fuse in the midline and form the neural tube (Fig. 1).[2] It had long been assumed that the neural tube starts to close in the cervical region, and that closure then extends both cranially and caudally from that site, like a zipper closing. However, recent animal and human data support the theory that closure of the neural tube actually occurs in separate regions, which then fuse (Fig. 2).[3-5] Four separate closure sites have been clearly demonstrated in mice and other animals, while human clinical data indicate the presence of 5 possible closure sites. NTDs likely result from either failure of closure in 1 site, or failure of 2 sites to meet. It is possible that the different closure sites are controlled by separate genes, which are susceptible to different environmental influences. Potential influences on neural tube closure include fetal gender, amniotic-fluid-nutrient levels, and genes implicated in genetic syndromes that include NTD.

Figure 1. Neural tube formation occurs during 3rd and 4th weeks of embyonic development. (Click on the thumbnail to zoom image)
thumbnail(A) Sequential transverse views illustrate how neural tube arises from neural plate anterior to primitive notochord.
thumbnail(B) Ectoderm cells form thick neuroepithelium that rises to begin formation of neural grove.
thumbnail(C) Surface ectoderm begins to close by fusion.
thumbnail(D) Complete closure of neural plate produces neural tube.
thumbnail(E) Neural crest cells migrate outward and develop into spinal ganglia.
Click here to view an animation (33K) of neural tube formation.

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Figure 2. (click here to zoom image) Closure of neural tube occurs in 5 separate regions, which then fuse. NTDs likely occur when 1 site fails to close or 2 sites fail to meet.

Back Risk Factors for NTDs

It has long been known that NTDs tend to occur more frequently in certain families. Similarly, parents who have had 1 child with an NTD are at significantly increased risk of having another child with the same or similar defect. These observations may reflect a shared environmental exposure and/or a specific genetic alteration imposing an increased susceptibility for this malformation. Family history is thus one of the most important risk factors for NTDs. Because isolated (nonsyndromic) NTDs are multifactorial, the degree of risk in an affected family never approaches that of an autosomal dominant or recessive disorder. The level of risk is directly related to the number of family members affected and their degree of relatedness to the fetus in question (Fig. 3).[6]

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Figure 3. (click here to zoom image) Level of risk that fetus will develop anencephaly or spina bifida is directly related to number and relatedness of family members with NTD. At lowest risk, with a 0.3% chance of NTD, is fetus of parents and relatives without NTD; at highest risk, with a 43% chance of NTD, is fetus of parents who both have NTD and have had 2 previous children with NTD.

NTDs are more common in certain geographic regions and among certain racial or ethnic groups. The UK has the highest frequency of NTDs, with an incidence of almost 1% compared with 0.2% in the US. China, Egypt, and India also have a very high incidence. The frequency of defects in these areas is probably related both to ethnic background and environmental influences, as illustrated by the fact that Indian Sikhs living in British Columbia, Canada, experience less than half the rate of NTDs of Sikhs living in India.[6-7]

One possible environmental influence on NTD formation is diet. Hibbard,[8] recognizing the importance of folates in both nucleotide synthesis and amino acid conversions, postulated more than 30 years ago that folate deficiency might contribute to fetal malformation. Hibbard and Smithells[9] were the first to demonstrate a significant association between NTDs and defective folate metabolism, an association that has since been proven by several animal studies.[10,11] Women whose pregnancies are complicated by fetal NTDs have been shown to have lower plasma levels of both vitamin B12 and folate than women whose pregnancies are unaffected.[12] Several clinical studies have suggested that folic acid supplementation prior to conception reduces the recurrence of fetal NTDs.[13-15] In 1991, the Medical Research Council Vitamin Study Research Group published the results of a large, prospective, randomized, double-blind study of folic acid supplementation conducted at 33 centers in 7 countries.[16] A total of 1817 women at high risk by virtue of a previously affected pregnancy were enrolled and randomly allocated to receive folic acid, other vitamins, folic acid plus vitamins, or placebo. Women assigned to take folic acid 4mg/day prior to pregnancy and through the twelfth week of gestation experienced a 72% reduction in their recurrence risk. A subsequent study by Czeizel and Dudas[17] showed that folic acid supplementation reduces the risk of a first occurrence as well.

The genetic basis for the relationship between folate metabolism and NTDs is now being investigated. The only metabolic reaction in human beings that requires both folate and B12 as cofactors is the conversion of homocysteine to methionine (Fig. 4). Mills and colleagues[18] demonstrated that blood levels of homocysteine are higher in mothers of children with NTDs, suggesting a defect in methionine synthase. Van der Put and associates[19] have reported a mutation in the gene for methylenetetrahydrofolate reductase in 16% of mothers and 10% of fathers (compared with 5% of control parents) and in 13% of children with spina bifida. The proportion of NTDs caused by these and other potential specific gene alterations is currently unknown.

thumbnail
Figure 4. (click here to zoom image) In investigating the relationship between folate metabolism and NTDs, researchers have found that the only metabolic reaction in human beings that requires both folate and B12 as cofactors is the conversion of homocysteine to methionine. Indeed, Mills' group discovered high blood levels of homocysteine in mothers of infants with NTDs.[18]

Several environmental agents have been implicated in NTD formation. Exposure must occur during the first 28 days of gestation, when the neural tube is forming, in order to produce the malformation. High first-trimester blood glucose levels, as might be found in a pregnancy complicated by insulin-dependent diabetes, impart an increased risk of developing an NTD. 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.[20] Elevated maternal core temperature during neural tube formation may also play a role. Maternal fever and using a sauna during the first trimester both increase the relative risk to 2.6% to 6.2%, although the duration and intensity of elevated body temperature necessary to produce an effect, and the embryologic mechanism, are unknown.[21] Certain medications are thought to be causative. Antiseizure medications, most notably valproic acid, impart a significantly increased malformation risk. Valproic acid use during the first trimester results in a 1% to 2% risk of having a fetus with spina bifida.[22] Aminopterin has been associated with a constellation of abnormalities that can include anencephaly or encephalocele.[23]

NTDs can also occur as part of a constellation of malformations (genetic syndrome, sequence, or association) or as the result of deforming processes. Genetic syndromes known to involve NTDs include Meckel-Gruber, Roberts', Jarcho-Levin, and HARDE syndromes, as well as trisomies 13 and 18 and triploidy. Cloacal exstrophy and sacrococcygeal teratoma may be associated with spina bifida, and amniotic bands may cause spina bifida or anencephaly.[24]

Back Screening and Diagnosis

Women who have already had a child with an NTD, or who have diabetes or any of the other known risk factors for NTDs, are readily recognized as being at increased risk and should be offered diagnostic tests during the second trimester of pregnancy. Unfortunately, only 5% of NTDs occur in families known to be at risk. Fully 95% of these malformations occur in families with no prior history.[16] Before the late 1970s, there was no way to identify women presumed to be at low risk, but who actually had a fetus with an NTD. In 1972, Brock and Sutcliffe[25] showed that amniotic fluid alpha-fetoprotein levels were much higher in pregnancies complicated by fetal anencephaly than in unaffected pregnancies. In 1973, Brock and colleagues[26] demonstrated that maternal serum alpha-fetoprotein levels were also elevated in affected pregnancies. Data from a large prospective trial of maternal serum alpha-fetoprotein screening published in 1977 showed that 88% of anencephaly cases and 79% of spina bifida cases could be identified by maternal serum alpha-fetoprotein levels 2.5 times higher than the normal median.[27] The utility of second-trimester maternal serum alpha-fetoprotein screening for fetal NTDs was subsequently confirmed by many other researchers and readily adopted by major centers in the US and Europe.[28-30]

Initially, women were offered a serum alpha-fetoprotein screening test; those with serum levels above the established cutoff were offered amniocentesis to determine amniotic fluid alpha-fetoprotein levels. Samples with elevated amniotic fluid levels were then subjected to assay for acetylcholinesterase, a neurally derived enzyme found in amniotic fluid only in association with an open NTD. The presence of an elevated amniotic fluid alpha-fetoprotein level together with a positive acetylcholinesterase assay is considered diagnostic. Using this protocol, up to 90% of all open NTDs could be identified.[31] Unfortunately, the positive predictive value of the maternal serum screening test (the percentage of positive tests associated with an abnormal outcome) is quite low (approximately 2%). This means that many women with elevated serum alpha-fetoprotein levels underwent amniocentesis unnecessarily. Although second-trimester amniocentesis is a relatively safe procedure, it is associated with a postprocedure loss rate of 1:200.

Fortunately, ultrasonographic equipment and technology have improved remarkably since maternal serum alpha-fetoprotein screening was adopted. Using modern equipment, an experienced sonographer should be able to identify at least 95% of all NTDs by doing a careful targeted examination of the fetus.[32] A targeted exam not only determines the fetal measurements and position, but also includes a detailed evaluation of all major organs. The cranium, brain, and spine (Figs. 5--10) can usually be readily visualized during such an examination. Amniocentesis can then be reserved for those patients in whom a defect is identified sonographically (for confirmation) and for those patients in whom visualization of the fetus is suboptimal and the examination is nondiagnostic.[33] Some authorities still recommend amniocentesis for all women with elevated maternal serum alpha-fetoprotein levels, reasoning that ultrasound is imperfect and that NTDs are associated with a small risk of fetal aneuploidy (detectable only by chromosome analysis of amniocytes).[34] The incidence of aneuploidy in fetuses judged on sonogram to be normal is approximately 0.61%.[32] The spectrum of chromosomal abnormalities discovered in such cases is different from that found in women undergoing amniocentesis because of their advanced maternal age. In fetuses found to have aneuploidy associated with an NTD, sex chromosome abnormalities account for one third of all cases while translocations and triploidy account for the remaining two thirds.

thumbnail
Figure 5. (click here to zoom image) Transverse cranial sonogram shows normal lateral ventricle.

thumbnail
Figure 6. (click here to zoom image) Frontal bossing ("lemon" sign) and ventriculomegaly (arrow) apparent in transverse cranial sonogram.

thumbnail
Figure 7. (click here to zoom image) Longitudinal view shows apparently normal spine.

thumbnail
Figure 8. (click here to zoom image) Sacral meningomyelocele (arrow) can be seen on this longitudinal view of fetal spine.

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Figure 9. (click here to zoom image) Longitudinal view of cranium and spine appears normal.

thumbnail
Figure 10. (click here to zoom image) Anencephaly can be seen on this longitudinal view of cranium and spine.

It is currently recommended that all pregnant women be counseled and then offered second-trimester maternal serum alpha-fetoprotein screening for fetal NTDs.[35] Women with levels above a predetermined cutoff (usually 2.0-2.5 multiples of the population median) should be referred for a targeted sonographic evaluation. All these issues (maternal serum alpha-fetoprotein detection rate and false-positive rate, risk of amniocentesis, etc.) should be discussed candidly with the patient at the time of her ultrasound, and the patient should decide whether or not to undergo amniocentesis based on the information provided and her own system of values and beliefs. Women known to be at increased risk to have a fetus with an NTD should plan to undergo both maternal serum screening and ultrasound evaluation, with amniocentesis performed at the discretion of the obstetrician-sonographer.

Back Management

Once an NTD is diagnosed, there are at present only 2 management options for the complicated pregnancy: terminating the pregnancy or continuing it. Unfortunately, no antenatal treatment is available to correct or ameliorate the effects of the malformation.

Anencephaly, exencephaly, and iniencephaly are lethal disorders for the fetus, but impose no increased risk to the mother's health. When women with these diagnoses elect to continue their pregnancies, they should receive the same prenatal care as any other gravida, with the exception that cesarean delivery for fetal indications is avoided. Because operative delivery will not change the outcome for the fetus, the mother should not be subjected to the increased risk imposed by this procedure.

A women whose fetus has spina bifida may benefit from counseling by a pediatric neurosurgeon, neurologist, or specialist in pediatric development or physical therapy before making a decision regarding the future of the pregnancy. The couple who is fully informed about the likely medical, surgical, and developmental problems to be faced by their infant is more likely to make the best decision for their family and to be prepared for their pregnancy outcome. Counseling about pregnancy termination should be provided regardless of the personal beliefs of the managing physician.

Women who decide to continue their pregnancies should be followed with serial sonographic examinations. Generally, delivery at term is optimal. However, rapidly increasing ventriculomegaly may prompt delivery before term, after documentation of pulmonary maturity, so that a ventricoloperitoneal shunt can be placed. The optimal timing of delivery has not been well established by the current literature, and each case should be managed individually in consultation with the neurosurgical and neonatal services. The best method of delivery is also controversial. The ultimate prospective randomized trial of vaginal versus cesarean delivery for fetuses with spina bifida has yet to be performed. All studies in the current literature are retrospective, and all suffer from various biases.[36-39] Theoretical advantages and disadvantages of each delivery method can be enumerated. A vaginal delivery avoids the trauma of a major operative procedure for the mother, and may provide some benefit to pulmonary function for the fetus. Cesarean section may theoretically avoid mechanical trauma to the fetal spine, and may avoid fetal infection associated with a vaginal delivery. Cesarean delivery also allows precise timing of the delivery so that the appropriate consultants can be available, although timely induction of labor might produce the same result. Until further guidance is offered by a well-designed research trial, the method of delivery should be determined by the team of physicians ultimately responsible for care of both mother and neonate.

Back Prevention

The best strategy to prevent NTDs involves planning for each pregnancy. As noted previously, folic acid supplementation prior to conception and through at least the first 8 weeks of pregnancy will substantially reduce both the occurrence and recurrence risks of a fetal NTD. All women contemplating a pregnancy should be advised to ingest a daily multivitamin containing folic acid starting before they attempt pregnancy. If folic acid supplementation is deferred until pregnancy is confirmed (usually at 3-5 weeks' gestation, at the earliest), the neural tube will already be formed and the beneficial effects of folic acid will be lost. Because many pregnancies are unplanned, folic acid fortification of grain has been proposed as a way to increase folic acid intake in the general population.

Patients known to be at increased risk should undergo individual counseling and possible alteration of their medical management prior to conception. Insulin-dependent diabetics should be counseled that maintaining their blood glucose levels within the normal range prior to conception and during organogenesis can reduce their risk of all fetal malformations to the background rate in the general population (2.4%). Patients with epilepsy who are taking valproic acid or aminopterin should be switched to a different antiseizure medication. Well in advance of attempting pregnancy, the woman's seizures should be well controlled on a new regimen that is safer to the fetus. Patients with high first-trimester fevers should be encouraged to take acetaminophen to reduce maternal temperature, and patients should be told to lower the risk of elevating their core temperature by limiting the time spent in a sauna or hot tub.

Back About the Author

Dr. Wenstrom is Associate Professor and Director, Prenatal Diagnosis, at the Center for Obstetric Research, Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, The University of Alabama, Birmingham, Ala.

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