**3. Etiology**

The development of nervous system is an embryonal process called neurulation. The primary neurulation is the first phase and includes the closure of the neural tube and thus forming brain and spinal cord. The second phase comprises formation of sacral and coccygeal segment and occurs around 26th day of gestation. Spina bifida is an incomplete closure of dorsal spinal structures and usually happens to appear between 17th to 30th postconceptional day [3]. The etiology of spinal dysraphism is multifactorial [22]. Although no clear etiology is known to result in either the open or closed forms, some regional adverse factors have been reported, primarily involving the mother at conception and early pregnancy. **Table 1** lists potential risk factors that are usually considered to be neural tube defects. Grewal et al. report in their study that maternal intake of the alcohol increased the risk for d-transposition of the great arteries, neural tube defects, and multiple cleft lip with or without cleft palate in infants. Smoking in this study was associated with a lower risk of neural tube defects [23]. Positive associations are observed between spina bifida and caffeine consumption and each caffeine source except caffeinated tea, which showed a negative association with the spina bifida. The association between caffeine consumption and anencephaly differed by maternal race and ethnicity. No dose effect of caffeine consumption was found [24]. Plasma levels of folate and vitamin B12 are independent risk factors for the occurrence of neural tube defects. This fact suggests that the enzyme methionine synthase is involved in the etiology of neural tube defects. The surprising finding is that folate and vitamin B12 levels, considered sufficient, continued to be a risk factor for an increased incidence of this defects. This finding is an incentive to re-evaluate daily doses of folate as well as

**7**

*Etiology and Pathophysiology of the Spina Bifida DOI: http://dx.doi.org/10.5772/intechopen.97467*

*Potential risk factors for neural tube defects (according to [3]).*

**Table 1.**

vitamin B12 [25]. The higher quality of the diet of expectant mothers is associated with a reduced incidence of neural tube defects. It is dietary approaches that could further reduce the risk of serious birth defects and complement existing efforts to promote the use of multivitamins during pregnancy [26]. Yazdy et al. refer that high insulin intake is risk factor for genesis of neural tube defects [27]. Results from experimental animals have suggested a role for methionine, an essential amino acid, in normal closure of the neural tube. Shaw et al. observed an approximately 30–40% reduction in neural tube defect-affected pregnancies among women whose average daily dietary intake of methionine was above the lowest quartile of intake. These reductions in neural tube defect risk were observed for both anencephaly and spina bifida, remained after adjustment for maternal race, ethnicity and education; and were observed irrespective of maternal level of folate intake [28]. Shaw al. observed elevated risk of neural tube defects associated with lower levels of total choline, and reduced risks with its higher level [29]. In the systematic review, Ray et al. report a moderate association between low maternal B12 status and the risk of fetal neural tube defects [30]. Studies report a reduction in the risk of neural tube disorders in infants and fetuses when mothers taking zinc in the preconception period. However, it has not been established whether the combination of nutrients or zinc alone is associated with a reduced incidence of neural tube disorders [31]. Maternal hyperthermia in early pregnancy is associated with increased risk for neural tube defects and may be a human teratogen [32]. Similarly, lower socioeconomic status and residence in a socio-economic status-lower neighborhood increased the risk of neural tube defect-affected pregnancy [33]. Although the excess risk for birth defects among children of mothers with diabetes mellitus is well documented, there are few data concerning the risk for specific malformations. No statistically significant differences were found among infants of mothers with gestational diabetes mellitus who did not require insulin during pregnancy. Insulin dependent diabetes mellitus is potential risk factor for malformations of central nervous system [34]. Women who experience stressful life events around the time of conception or early gestation may be at increased risk of delivering infants with certain congenital anomalies. For example, in Mexican population in the United States, the occurrence of stressful life events was associated with the risk of neural tube defects. These findings suggest that stress may increase risk in populations with poor nutritional status and poor economic resources [35, 36]. It is likely that not all malformations of the human fetus associated with valproate exposure during pregnancy have a comparable quantitative dose relationship. The reducing of the valproate dose in early pregnancy will provide more effective protection against the spina bifida and other types of fetal malformations [37]. Lupo et al. found an association between environmental level of benzene and the spina bifida. Mothers

**Maternal nutrition Other maternal factors Environmental factors** Alcohol and caffeine use Smoking Ambient air pollution Insufficient folate intake Low socio-economic status Indoor air pollution Low dietary quality Infections and hyperthermia Nitrate-related compounds

Elevated glycemic load Pregestational diabetes Organic solvents Low methionine and zinc intake Pregestational obesity Pesticides

Low serum choline level Psychosocial stress Polycyclic hydrocarbons Low vitamin B12 and C level Valproic acid use Disinfectant in drinking water


**Table 1.**

*Spina Bifida and Craniosynostosis - New Perspectives and Clinical Applications*

impact on the epidemiology of the spina bifida. The prenatal detection rate of spina bifida is high, and most cases of spina bifida are isolated and have a normal karyotype [19]. Omission of elective terminations clearly underestimates prevalence and may bias risk estimations in etiologic studies. Compared with women who delivered liveborn/stillborn infants with neural tube defects, women who electively terminated neural tube defects-affected pregnancies were disproportionately white, were more highly educated, had higher incomes, and used vitamins containing folic acid more often [20]. The European network of population-based registries for epidemiological surveillance of congenital anomalies (EUROCAT), collects data on pregnancy terminations in addition to live and stillbirths, generating particularly comprehensive prevalence data for neural tube defects and other malformations. During four years (2003 to 2007), this register reports an overall prevalence of serious congenital anomalies of 23.9 per 1,000 live births. As many as 80% of children with severe congenital anomalies were born alive. The mortality of these children in the first week of life was 2.5%. The abortion was performed after prenatal diagnosis in 17.6% of cases. Congenital anomalies mainly concern newborns with specific medical and social care needs. The prevalence of chromosomal abnormalities was 3.6 per 1,000 live births. Their presence led to a 28% incidence of stillbirths or their diagnosis conditioned 48% of all terminations. The most common non-chromosomal subgroups were congenital heart defects, limb anomalies, nervous system disorders and urinary system anomalies. In 2004, perinatal mortality associated with congenital anomaly was 0.93 per 1000 births, and terminations of pregnancy following prenatal diagnosis 4.4 per 1000 births, with considerable country variation. Primary prevention of congenital anomalies in the population based on controlling environmental risk factors is a crucial policy priority, including pre-conceptional care and whole

The development of nervous system is an embryonal process called neurulation. The primary neurulation is the first phase and includes the closure of the neural tube and thus forming brain and spinal cord. The second phase comprises formation of sacral and coccygeal segment and occurs around 26th day of gestation. Spina bifida is an incomplete closure of dorsal spinal structures and usually happens to appear between 17th to 30th postconceptional day [3]. The etiology of spinal dysraphism is multifactorial [22]. Although no clear etiology is known to result in either the open or closed forms, some regional adverse factors have been reported, primarily involving the mother at conception and early pregnancy. **Table 1** lists potential risk factors that are usually considered to be neural tube defects. Grewal et al. report in their study that maternal intake of the alcohol increased the risk for d-transposition of the great arteries, neural tube defects, and multiple cleft lip with or without cleft palate in infants. Smoking in this study was associated with a lower risk of neural tube defects [23]. Positive associations are observed between spina bifida and caffeine consumption and each caffeine source except caffeinated tea, which showed a negative association with the spina bifida. The association between caffeine consumption and anencephaly differed by maternal race and ethnicity. No dose effect of caffeine consumption was found [24]. Plasma levels of folate and vitamin B12 are independent risk factors for the occurrence of neural tube defects. This fact suggests that the enzyme methionine synthase is involved in the etiology of neural tube defects. The surprising finding is that folate and vitamin B12 levels, considered sufficient, continued to be a risk factor for an increased incidence of this defects. This finding is an incentive to re-evaluate daily doses of folate as well as

**6**

population approaches [21].

**3. Etiology**

*Potential risk factors for neural tube defects (according to [3]).*

vitamin B12 [25]. The higher quality of the diet of expectant mothers is associated with a reduced incidence of neural tube defects. It is dietary approaches that could further reduce the risk of serious birth defects and complement existing efforts to promote the use of multivitamins during pregnancy [26]. Yazdy et al. refer that high insulin intake is risk factor for genesis of neural tube defects [27]. Results from experimental animals have suggested a role for methionine, an essential amino acid, in normal closure of the neural tube. Shaw et al. observed an approximately 30–40% reduction in neural tube defect-affected pregnancies among women whose average daily dietary intake of methionine was above the lowest quartile of intake. These reductions in neural tube defect risk were observed for both anencephaly and spina bifida, remained after adjustment for maternal race, ethnicity and education; and were observed irrespective of maternal level of folate intake [28]. Shaw al. observed elevated risk of neural tube defects associated with lower levels of total choline, and reduced risks with its higher level [29]. In the systematic review, Ray et al. report a moderate association between low maternal B12 status and the risk of fetal neural tube defects [30]. Studies report a reduction in the risk of neural tube disorders in infants and fetuses when mothers taking zinc in the preconception period. However, it has not been established whether the combination of nutrients or zinc alone is associated with a reduced incidence of neural tube disorders [31]. Maternal hyperthermia in early pregnancy is associated with increased risk for neural tube defects and may be a human teratogen [32]. Similarly, lower socioeconomic status and residence in a socio-economic status-lower neighborhood increased the risk of neural tube defect-affected pregnancy [33]. Although the excess risk for birth defects among children of mothers with diabetes mellitus is well documented, there are few data concerning the risk for specific malformations. No statistically significant differences were found among infants of mothers with gestational diabetes mellitus who did not require insulin during pregnancy. Insulin dependent diabetes mellitus is potential risk factor for malformations of central nervous system [34]. Women who experience stressful life events around the time of conception or early gestation may be at increased risk of delivering infants with certain congenital anomalies. For example, in Mexican population in the United States, the occurrence of stressful life events was associated with the risk of neural tube defects. These findings suggest that stress may increase risk in populations with poor nutritional status and poor economic resources [35, 36]. It is likely that not all malformations of the human fetus associated with valproate exposure during pregnancy have a comparable quantitative dose relationship. The reducing of the valproate dose in early pregnancy will provide more effective protection against the spina bifida and other types of fetal malformations [37]. Lupo et al. found an association between environmental level of benzene and the spina bifida. Mothers

living in census tracts with the highest benzene levels were more likely to have offspring with the spina bifida than women living in census tracts with the lowest levels [38]. Waller et al. report moderate positive association of maternal obesity with 7 of 16 categories of birth defects. The mechanisms underlying these associations are not yet understood but may be related to undiagnosed diabetes mellitus [39]. Severe obesity has been associated with larger risks of the spina bifida incidence. Underlying mechanisms that have been suggested including aberrant glucose control, oxidative stress, and metabolic syndrome [40]. Higher water nitrate intake was associated with several birth defects in offspring but did not strengthen associations between nitrosatable drugs and birth defects [41]. Cordier et al. report the association between exposure to glycol ethers and neural tube defects, multiple anomalies, and cleft lip [42]. Pesticide exposures were associated with risk of neural tube defects, especially use of pesticides at home and a peri-conceptional residence within 0.25 mile of cultivated fields [43]. Persistent organic pollutants have been associated with a wide range of adverse health effects. Elevated placental concentrations of polycyclic aromatic hydrocarbons, dichlorodiphenyltrichloroethane isomers, and α-hexachloro-cyclohexane are associated with increased risks of neural tube defects [44].

Considerable evidence points to a major genetic component in the spina bifida causation, raising the question of which genes are implicated. In animal spina bifida models more than 40 genetic strains were detected to be associated with this disorder. In some human patients were detected various genetic alterations of coding regions of planar cell polarity genes pathway and genes encoding folate metabolism. The study of folate and its association with neural tube defects is an ongoing endeavor that has led to numerous studies of different genes involved in the folate metabolism pathway, including the most commonly studied thermolabile C677T mutation in the methylenetetrahydrofolate reductase gene [3, 45, 46]. Most of observed genetic alterations are sporadic (non-syndromic), only less than 10% of cases are syndromic, connected with genetic disorders such as trisomy 13 or 18. Up to date evidence supports a theory of a multi-factorial origin of neural tube defects as a consequence of both, genetic and non-genetic factors [47]. Recent studies of mouse mutant with transformation related protein 53 showed that exencephaly susceptibility depends on the presence of two X chromosomes, not the absence of the Y chromosome. Involvement of genetic factors in etiology is supported by evidence that the risk for siblings of spina bifida patient is 2–5%, representing 20 to 50-fold higher risk compared to the general population prevalence of 1 per 1000. Relatives of 2nd and 3rd line display lower risk compared to 1st line relatives, though still increased compared to standard population risk. Woman who has child with spina bifida has approximately 3% risk for another pregnancy affected by spina bifida, risk arises to 10% after two affected pregnancies. The agreement of neural tube defects is higher in monozygotic and dizygotic twins of the same sex compared to twins of the opposite sex. Female excess among cranial neural tube defects is an epigenetic phenomenon whose molecular investigation will produce insight into the mechanisms underlying neural tube defects [3, 48]. Trisomy 18 is the most commonly associated aneuploidy with open neural tube defects. Other genetic disorders include Meckel-Gruber syndrome, Jarcho-Levin dysplasia, HARD (hydrocephalus, agyria and retinal dysplasia), trisomy 13, PHAVER syndrome (pterygia, heart defects, autosomal recessive inheritance, vertebral defects, ear anomalies and radial defects), VATER syndrome (vertebral anomalies, anal atresia, trachea-esophageal fistula and renal abnormalities), and X-linked neural tube defects among others. A significant number of fetuses with open defects are chromosomally abnormal. Although prenatal chromosome analysis should be considered in all cases, prenatal ultrasound seems effective in identifying those fetuses with an underlying

**9**

**Figure 2.**

*The process of the gastrulation (author's archive).*

*Etiology and Pathophysiology of the Spina Bifida DOI: http://dx.doi.org/10.5772/intechopen.97467*

neural tube defects.

**4. Pathophysiology**

chromosomal abnormality. It is questionable how many genes in the human genome pose a risk of neural tube defects. Studies often draw conflicting conclusions due to limitations in the design of studies that affect the strength of statistical analysis. Association studies and sequencing of the entire exome or genome are a way to identify genes that affect the incidence of human neural tube defects [16, 49, 50]. If a prenatal diagnosis of myelomeningocele is suspected, karyotype and genetic consultation should be obtained. Multidisciplinary approach is necessary to treat and support this malformation which is a huge burden on the patient, family, and the society. The most of suspected etiological factors does not have strong evidence or occur less frequently. This underlines to theory of multifactorial etiology of

The development of the normal spinal cord from the second to the sixth week of pregnancy includes gastrulation and primary and secondary neurulation. During the first stage of gastrulation, the endoderm and ectoderm form a bilaminar embryonic disc (**Figure 2**). Cell division and migration lead to the formation of a mesoderm and a trilaminar disk is formed. The interaction of the notochord with the ectoderm creates a neuroectoderm. The beginning of the neural plate is in the midline and then extends in the proximal and caudal directions. The pathological effects during primary neurulation can lead to the spinal dysraphism. Part of the primary neurulation is the formation of nerve folds - the nerve groove. By joining the nerve folds, the nerve plate changes into a neural tube. Closure of the cranial and caudal openings of the neural tube represents the end of the process of primary neurulation (**Figure 3**). Disorder of the closure of the caudal neural tube causes the formation of a plaque (exposed nerve tissue). The existence of a neural plaque is a differential feature between myelocele and myelomeningocele [51]. Pluripotent cells forming the caudal end, forms vacuoles and neurons. Their cavitation leads to the formation of a central canal. Apoptosis of said cells leads to the formation of the conus medullaris, filum terminale and ventriculus terminalis. The final closure of the caudal neuropore leads to the transformation from the primary neurulation to the secondary neurulation. During secondary neurulation, the ectoderm and part of the endoderm forms the medullary cord. Two types of cells develop from the medullary epithelium - neuroblasts and spongioblasts. Neuroblasts differentiate

*Etiology and Pathophysiology of the Spina Bifida DOI: http://dx.doi.org/10.5772/intechopen.97467*

chromosomal abnormality. It is questionable how many genes in the human genome pose a risk of neural tube defects. Studies often draw conflicting conclusions due to limitations in the design of studies that affect the strength of statistical analysis. Association studies and sequencing of the entire exome or genome are a way to identify genes that affect the incidence of human neural tube defects [16, 49, 50]. If a prenatal diagnosis of myelomeningocele is suspected, karyotype and genetic consultation should be obtained. Multidisciplinary approach is necessary to treat and support this malformation which is a huge burden on the patient, family, and the society. The most of suspected etiological factors does not have strong evidence or occur less frequently. This underlines to theory of multifactorial etiology of neural tube defects.
