Neural tube defects (NTDS) are congenital structural abnormalities of the brain and spine that can occur alone or in conjunction with other malformations, or as a manifestation of a genetic syndrome. The incidence of NTDS alone occurs at a rate of approximately 1.4-2/1000 pregnancies and is the second most common congenital anomaly in the world (with cardiac anomalies leading the way). Approximately 4,000 fetuses are affected each year in the United States, and one-third of these fetuses are induced or spontaneously aborted. Anencephaly accounts for half of all neural tube defects, and these patients do not survive. 80-90% of patients with spina bifida survive with varying degrees of disability after treatment. More importantly, neural tube defects are one of the few birth defects for which early prevention, widespread prenatal screening and diagnosis are possible and prenatal treatment is being attempted.
Background
Embryology
The neural plate appears in the third week of gestation, after which the neural folds form and fuse in the midline to form the neural tube. Available studies have shown that neural tube closure in animals and humans can occur at multiple sites of subsequent fusion, and the defect may be due to failure of closure at one site or failure of fusion between two sites. Normally, neural tube closure is completed by the end of the fourth week after conception (six weeks after the last menstrual period), when many people are unaware that they are pregnant.
Pathophysiology
Neural tube defects can be divided into defects of the cranial spine (see Table 1), and cranial defects include abnormalities in the formation of the skull, scalp, and brain tissue. These abnormalities, with the exception of mild brain expansion, are lethal malformations. Spina bifida refers to caudal abnormalities of the neural tube, including abnormalities of the spinal cord, cerebrospinal membrane, and spine, and patients survive in most cases. Neurotubular defects affecting the spine combined with ventricular enlargement are usually the result of type II Arnold-chiari malformation[3,6,7] .
Clinical outcome of neural tube defects
Increased intracranial pressure due to ventricular enlargement can be relieved by placement of ventriculo-abdominal drainage. Most newborns with spina bifida and ventricular enlargement require drainage within the first year of life, and at least two-thirds of them require multiple emergency repeat drains during their lifetime[8,9] . The deterioration of Arnold-chiari is partly due to the small posterior cranial fossa, which leads to severe or even fatal neurological restriction and consequent respiratory and swallowing abnormalities, and surgical relief of posterior cranial fossa pressure is extremely risky.
Aggressive treatment after birth includes surgical closure of the defect within the first 48 hours of life. The degree of recovery of motor and sensory limitations due to spina bifida can be predicted by the location of the lesion, with the higher the location, the worse the prognosis. Most patients with lesions at the thoracic level are wheelchair dependent only, while 90% of patients with lesions at the sacral level can walk. In a study that followed 101 children with cerebrospinal spinal bulge, 85% of those with quadriceps function (normal L2, L3, L4) could walk independently, and the other 8% could walk at home and use a wheelchair only in public. In contrast, only 9% of those with quadriceps function deficits walked occasionally.
Most patients with spina bifida have impaired rectal and bladder function, even if the lesion is low. Urinary tract infections and stones are common chronic conditions and can even lead to death from abscesses and renal failure[12] . Sexual dysfunction is due to loss of sensation in the genital tract and difficulties with erection and ejaculation[13] . Endocrine abnormalities, embolism spinal cord, hunchback, spinal cord cavitation, and medullary cavitation can be caused by neurological defects as well as their repair. At least one-third of NTD latexes are severely allergic and have fatal reactions upon exposure[3] .
Although most children with spina bifida have a normal IQ, their intelligence is affected[6] . Several authors have reported that without elevated intracranial pressure, there is no correlation between ventricular volume and intelligence in children with spina bifida[8,15] , but it may occur that elevated intracranial pressure due to neurological infection or poor drainage can cause reduced neurological function. In a study of 167 children with spinal dysraphism, the mean IQ was 102 for those without hydrocephalus, 95 for those with hydrocephalus requiring shunt surgery, and 73 for those with shunt surgery and a history of infection[15] . IQ loss has also been associated with intraoperative complications and other neurosurgical procedures.
Etiology
Independent NTDs are the result of a combination of genetic susceptibility and environmental factors[16] . Evidence of genetic susceptibility is that NTDs are predisposed in some families, with a significant increase in the analysis of parents who have had a child with an NTD having the next child with the same or similar defects (Table 2) [17] . However, only 5% of NTDs have a positive family history and more than 90% have no positive family history, probably because individuals with genetic susceptibility were not exposed to an environment sufficient to cause defects in their offspring. Therefore, most people do not realize that they are high-risk individuals until they have an abnormal child.
Only environmental influences during the first 28 days of gestation, when the neural tube is formed, can cause defects. Known factors associated with NTDs include: geography, race, diet, teratogen exposure, maternal diabetes, and maternal hyperthermia.19-23 Areas with a high prevalence of NTDs include the British Isles, China, Egypt, and India. Certain ethnicities are also at high risk, for example, a 5-year population-based data from the California region showed that Spanish women (1.2/1000, 95% CI 1.04-1.21), Caucasian women (0.96/10,000, 95% CI 0.89-1.04) were at high risk, African-American (0.75/10,000, 95% CI 0.59- 0.91) and Asian women (0.75/10,000, 95% CI 0.60-0.90) were at low risk. Some ethnic differences may reflect differences in geography, diet, and genetic susceptibility. For example, tin clients living in India have a twofold higher incidence than those living in Canada[17] .
Independent NTDs are often associated with abnormal folate metabolism, which will be discussed later. NTDs in genetic syndromes are more likely to have a genetic cause rather than abnormal folate metabolism, which include Meckel-gruber, Robert, Jarcho-levin and HARD syndromes, as well as trisomy 13, trisomy 18, and triploidy. Cloacal ectopia? and sacrococcygeal teratomas are often seen in conjunction with spina bifida, and amniotic bands can lead to spina bifida and anencephaly.
Significance of Folic Acid
The most important influence on NTD is the diet, especially the intake of folic acid. It has long been known that pregnant women carrying NTDs have lower plasma B12 and folate levels, and many of the factors that contribute to NTDs such as phenytoin sodium, aminopterin, and carbamazepine are known to affect folate metabolism. Some studies have shown that pre-pregnancy folic acid supplementation decreases the recurrence of fetal NTD[26-29] . However, the benefits of folic acid were not widely recognized until 1991 when the Medical Research Association Vitamin Group published a large, prospective, randomized, double-blind trial of folic acid supplementation at 33 centers in seven countries.30 A total of 1817 high-risk women with a history of NTD pregnancies were enrolled in the trial and randomly assigned to receive folic acid, other vitamins, both, and neither groups. As a result, the risk of recurrence was reduced by 72% from pre-pregnancy to 12 weeks of gestation with 4 mg of folic acid daily (OR 0.28,95% CI 0.15-0.53).
The Medical Research Associates study included women limited to those with a history of NTD pregnancy, which accounted for 5% of NTDs. Another double-blind, placebo-controlled randomized study found that folic acid supplementation before and after conception also reduced the first incidence of NTDs[31] . This was followed by a number of studies confirming the prevention of NTD occurrence and recurrence by folic acid supplementation before and after conception[32,33] .
The genetic basis of the relationship between folate metabolism and NTD is being investigated. The most important metabolic reaction requiring folic acid is the conversion of homocysteine to methionine, and there is evidence that this pathway is closely related to the origin of NTDs. It has been shown that affected offspring of parents who have had NTDs are more likely to carry mutations in the locus encoding tetrahydrofolate reductase; for example, in the Netherlands, 14-16% of mothers, 10-15% of fathers, and 13-18% of children with spina bifida are purely germline with mutations in tetrahydrofolate reductase, compared to 5% of the normal population[34-36] . Other mutations in this enzyme have similar effects[36] , so it seems likely that folic acid supplementation will help overcome the enzyme defect and produce more normal levels of homocysteine and sufficient methionine[21] , which is important for its provision of methyl groups, which are necessary for gene regulation and many metabolic reactions for tissue growth and development.
[Clinical considerations and recommendations].
Is folic acid supplementation useful for NTD prevention?
Folic acid is currently recognized to be beneficial for the prevention of independent NTDs, but must be taken from preconception until the first 4 weeks of fetal development. Because the neural tube is largely formed one month after the last menstrual period, it is not sufficient to start folic acid after a known pregnancy. Although a folic acid-rich diet should be recommended at childbearing age, some studies have concluded that folic acid in food does not elevate plasma folic acid levels, so additional supplementation is recommended. Studies that include specific recommendations for dosing are underway.
In 1991, the Centers for Disease Control and Prevention recommended that all women with a history of NTD pregnancies take 4 mg of oral folic acid before and during the first trimester after conception. The following year, the American Public Health Association recommended 400 μg oral folic acid daily for all women with potential pregnancies, and this recommendation was adopted by many societies, including the Obstetrics and Gynecology Society.
In fact few people routinely take folic acid supplements, and although women take folic acid supplements when they become pregnant, more than half have unplanned pregnancy histories, and the neural tube is formed before these people know they are pregnant and before they take folic acid supplements, so most do not benefit from this preventive recommendation. From January 1998, the FDA required folic acid to be formulated in cereals. As a result of this requirement, women on a standard diet consumed an average of 200 μg more folic acid per day[40] .
Despite the fact that cereal-formulated folic acid has increased folic acid intake across the United States, many authorities believe that current formulation levels are insufficient to prevent NTDs. μg of folic acid per day reduces NTD by only 20%[41] . This result is being supported by the American Public Health Association. The latter confirmed that NTDs in the United States have been reduced by only 19% since the implementation of the cereal formula[42] .
A daily supplementation of 400 μg of folic acid is now recommended for women of childbearing age. Available data calculations predict that the 400 μg folic acid recommendation for low-risk women reduces NTDs by 36%, and this study also found that the current recommendation of 4 mg for high-risk women reduces NTDs by 82% and 5 mg reduces NTDs by 85%[41] .
Supplementation at high doses is considered a minimal risk factor, and even very high doses of folic acid are nontoxic and are rapidly excreted via urine. There was concern that folic acid supplementation would mask the symptoms of pernicious anemia as well as delay treatment; however, folic acid does not mask the typical neuropathy of this disease. Currently, 12% of pernicious anemias present with only neuropathic symptoms[43] , and this percentage increases with folic acid supplementation, but there is no evidence that starting folic acid supplementation after developing pernicious anemia leads to irreversible damage[44] . A small proportion of women taking anticonvulsant drugs (phenytoin sodium, aminopterin, carbamazepine) have low blood levels and an increased frequency of convulsions during folic acid administration[45] , so blood levels need to be tested and doses increased to avoid this complication.
Some multivitamins and most prenatal vitamins contain 400 μg of folic acid, and high folic acid levels should be achieved by taking increased doses of folic acid rather than too many multivitamins; in particular, high doses of vitamin A are teratogenic, and pregnant women should not take more than 5000 IU per day, which is exactly the amount that a multivitamin neutralizes.
Which NTD is not affected by folic acid?
There is only limited evidence that folic acid supplementation does not reduce the risk of having an NTD in women who are hyperglycemic at the end of pregnancy, have a high temperature in early pregnancy, or are taking valproic acid. In hyperglycemic women, the mechanism is unclear and may be related to the inhibition of fetal glycolysis, defective function of arachidonic acid or inositol during embryonic development or blastocyst transformation[23] . Although the intensity and timing of the effects and the mechanism of action are unclear, it has been determined that maternal fever and sauna during early pregnancy increase the risk of NTD (2.6-6.2-fold) and that women taking valproic acid during early pregnancy have a 1-2% risk of having spina bifida, by a different mechanism than other anticonvulsants[19] . NTD in fetuses with aneuploidy or genetic syndromes may be the result of characteristic genetic abnormalities and cannot be prevented by folic acid.
Is maternal plasma AFP testing useful in predicting NTD?
Maternal amniotic fluid and blood AFP (MSAFP) is elevated in 89-100% of NTD fetuses[47] . Many large prospective MSAFP screening studies have shown that most NTD pregnancies can be detected by elevated MSAFP, usually more than 2.5 times the median singleton pregnancy.
Because more than 90% of children with NTD have no family history and no apparent risk factors, MSAFP may also detect affected fetuses as part of aneuploidy screening. Most screening programs strive to find more positive fetuses without unduly increasing the false-positive rate, which requires a trade-off between sensitivity and specificity. The false-positive rate can be reduced by ultrasound verification of gestational week prior to screening for MSAFP, identification of multiple fetuses and intrauterine death.
How is the NTD diagnosis established?
Maternal plasma AFP testing is an effective means of screening for NTDs and should be promoted in pregnant women unless she is ready to undergo amniocentesis for prenatal diagnosis of chromosomal abnormalities and genetic disorders. MSAFP is a screening test and therefore has a high false-positive rate, with only 2% of positive results having NTDs, and a diagnostic test is required. MSAFP levels higher than expected (usually 2-2.5 MOM) should Genetic counseling and diagnostic testing are recommended. Women with known high-risk factors, including prior pregnancies with NTDs, positive family history, medication use, diabetes, or other risk factors, may proceed directly to diagnostic testing. Because these high-risk women will undergo diagnostic testing regardless of MSAFP results, MSAFP is less meaningful as a screening tool, but is still useful for evaluating the fetus.
The traditional screening test for women with a positive MSAFP result is amniocentesis. If AFP is elevated in the amniotic fluid, it is checked for the presence of acetylcholinesterase. In a study of nearly 10,000 singleton pregnancies at 14-23 weeks with known pregnancy outcomes, amniotic fluid acetylcholinesterase levels were found to detect 100% anencephaly, 100% open spina bifida, and 20% abdominal wall defects, with a false positive rate of 2.2/1000.
The advantage of amniocentesis is that amniotic fluid can be obtained to examine fetal karyotype. It has been suggested that elevated MSAFP can independently predict a high risk of fetal aneuploidy[53] . In pregnancies with elevated MSAFP, the incidence of fetal aneuploidy was 0.61% for normal ultrasound and 16% for abnormal ultrasound, respectively[54, 55] . Amniocentesis performed in all high-risk women detects 98% of NTDs and finds 100% of aneuploidy. However, given the high false-positive rate of MSAFP screening, universal amniocentesis in all high-risk women would mean that many would endure unnecessary amniocentesis, despite the relative safety of amniocentesis in midtrimester, with a postoperative miscarriage rate of approximately 1 in 200.
Ultrasound technology has continued to advance since MSAFP screening was introduced. Obstetric ultrasound centers with specialists have excellent sensitivity and specificity in diagnosing NTDs, especially in high-risk women. Many centers already offer special ultrasound as a diagnostic test for high-risk women[57] . In experienced sonographers, ultrasound alone has a sensitivity of 97% and a specificity of 100% for the diagnosis of NTD[57] . However, in less experienced sonographers, ultrasound is only a screening method with a high false-negative rate, and in a multicenter screening of low-risk women, only 35% of malformations were detected in tertiary hospitals and 13% in non-tertiary hospitals, with 7 out of 8 NTDs detected.
To gain the advantages of both tests and to reduce the risk, many centers are now starting with a special ultrasound for all high-risk pregnancies, followed by amniocentesis for only a subset of them. If no fetal defects are found after high-quality ultrasound, the advantages and disadvantages of amniocentesis and special ultrasound can be discussed with the patient. Considering the risk associated with MSAFP levels or family history, as well as the quality of the special ultrasound, the patient’s age, and wishes, the decision to perform an invasive test may be made. Many high-risk patients forgo amniocentesis after re-evaluation of special ultrasound. Amniocentesis is indicated for confirmation when fetal defects are found or when the fetus is found to be unpromising or when ultrasound is not helpful for diagnosis[59] . The risk of fetal abnormality is 3.4% for an MSAFP level of 2.5 MOM and increases to 40.3% for an MSAFP level of 7 MOM (Table 3) [60]. Some pregnant women with high risk of NTD also opt for amniocentesis because the fetus is aneuploidy high risk. Some experts question the use of ultrasound as a diagnostic tool and recommend amniocentesis in all cases of elevated MSAFP.
Are there special considerations for the obstetric management and delivery route of NTD fetuses?
Most fetuses with spina bifida will be delivered at term unless obstetric intervention is performed. Fetal spina bifida does not increase the risk of utero-placental underperfusion, hypohydramnios, and anencephaly is associated with hyperhydramnios because of reduced swallowing. There is no evidence that prenatal screening for NTD alone improves pregnancy outcomes. Moreover, structurally abnormal fetuses often present with unexplained fetal heart abnormalities[64] . Serial ultrasonography to detect fetal development and ventricular volumes can be helpful in planning delivery.
Fetuses with spina bifida should be delivered in a hospital with neonatal intensive care and the ability to manage spinal defects and emergency complications, which has been shown to result in a slightly better outcome[65] . Because of the risk of developing a severe or even life-threatening allergy to latex in patients with NTD[3] , latex-free gloves are mandatory for handling newborns. Full-term delivery is usually preferred. However, once lung maturation can be confirmed, labor can be induced and a ventriculo-abdominal shunt left in place before full term for fetuses with rapidly enlarging ventricles. Each case should be consulted with experienced specialists and neurosurgical and neonatal facilities.
Breech presentation due to neurological dysfunction or an enlarged head with hydrocephalus is common in pregnant women with combined spina bifida, and cesarean delivery is the accepted standard for breech presentation NTDs[66] . The optimal mode of delivery for cephalic previa remains controversial. There are no prospective randomized studies comparing vaginal delivery with cesarean delivery in fetuses with spina bifida cephaladis, and all current literature is retrospective and biased. At least five studies, representing a total of 400 patients, concluded that vaginal delivery was not detrimental to neonatal outcome, while another large study of 200 patients held the opposite view [66-71].
Studies in this area are also limited by the lack of long-term follow-up, which is necessary to evaluate the effectiveness of treatment because failure to recover neurological function is still common with early treatment of NTDs. Because it is not known whether and how the mode of delivery affects the newborn, decisions about the timing and mode of delivery should be made in consultation with specialists experienced in this area, including maternal and infant medicine, neonatologists, and pediatric neurosurgeons.
Does it make sense to operate on NTD fetuses?
The “second strike hypothesis” suggests that the possible causes of neurological damage in NTDs are developmental abnormalities leading to open spina bifida in the first strike and infection and damage to the neural tissue due to exposure to the amniotic fluid, fetal activity, contact with the uterine wall, and pressure of delivery in the second strike. Once the first blow has occurred, its effects cannot be eliminated by prenatal intervention, but researchers are attempting to close the fetal spina bifida in utero, theoretically preventing damage from the second blow[72] .
From 1997-2002, approximately 220 cases of intrauterine spina bifida were performed in four centers in the United States. These studies were not randomized and usually selected for fetal lesion location below the thoracic spine. Data from this cohort study did not suggest improvements in urination, defecation, or walking ability[73,74] . These children, however, appear to have fewer or at least delayed bypass procedures. They appear to have improved in the degree of brain herniation that forms in the hindbrain after in utero surgery, which, if confirmed, contributes to the severe morbidity and mortality due to worsening type II Arnold-chiari malformation[75,76] . Because of selection bias in the cohort and substandard neurosurgical follow-up, it is difficult to say whether the medical need for shunting is truly reduced or whether brain herniation is reduced, which is consistent with improved function.
Maternal-fetal surgery is risky, and the mother bears double all the risks associated with the procedure (anesthesia complications, bleeding, bladder injury, chorioamnionitis). First, incision of the uterus at the end of the second trimester to remove the fetus requires a cesarean section for this and subsequent pregnancies in this patient because of the increased risk of uterine rupture by hysterotomy[77] .
The most obvious potential complications for the fetus are preterm delivery and secondary complications[76] . Fetuses undergoing intrauterine surgery are delivered at approximately 33 weeks, with approximately 40% of them delivered before 32 weeks[75,76,78] . A study of 29 cases undergoing intrauterine surgery showed a preterm delivery rate of 50%, premature rupture of membranes of 28%, and 48% with low amniotic fluid, while only 4% of the control group had these complications[78] . A study of 33 intrauterine procedures with known neurological outcomes found that 21% of fetuses had additional central nervous system damage[79] . Cofactors included slow intraoperative fetal heart rate, significant maternal blood loss, maternal expiration or hypertension, neonatal hypertension, uterine contractions, and the application of terbutaline and nitroglycerin.
Information on long-term complications in mothers and newborns undergoing intrauterine surgery is just beginning to be collected, and data from 70 cases at a large fetal surgery center suggest that intrauterine surgery has no long-term effect on fertility[80] . However, an increased incidence of early cord-like cord has been reported in fetuses undergoing intrauterine repair of cerebrospinal spinal bulge[81] . Parents must understand these risks and be aware of other potential complications prior to surgery.
The ethical issues related to intrauterine surgery in fetuses with spina bifida are complex and are currently being studied. a prospective, randomized, prenatal surgical repair of spina bifida study started in 2003 and supported by the national health ministry is expected to address this issue.
Summary of Recommendations
The following recommendations are based on good and consistent scientific evidence (A): Periconceptional folic acid supplementation is recommended to reduce the incidence and recurrence of NTD. Due to the inadequacy of nutritional sources alone, 400 μg of folic acid supplementation daily is recommended for low-risk women. Considering the toxicity of vitamin A, high-dose folic acid should not be obtained from an overdose multivitamin. For high-risk women who have given birth to an NTD, a daily supplementation of 4 mg folic acid is recommended. Maternal serum alpha-fetoprotein is effective in screening for NTD and is recommended for all pregnant women.
The following recommendations are based on limited or inconsistent scientific evidence (B).
Maternal serum AFP elevation should be followed by ultrasonography to further evaluate the risk of NTD.
NTD fetuses should be delivered in a hospital that can manage all neonatal complications.
The following recommendations are based on preliminary consensus and expert opinion (C).
The ideal dose of folic acid supplementation has not been evaluated in prospective clinical studies. The current recommendation is 400 μg of folic acid supplementation daily for women of childbearing age.
The mode of delivery for NTD fetuses varies from person to person, and there are no data to suggest which mode has better outcomes.