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Similar rhythms of seasonal conceptions in neural tube defects and schizophrenia: a hypothesis of oxidant stress and the photoperiod.

BACKGROUND: Numerous studies have found that people with schizophrenia tend to be born most often in late winter and least often in late summer. The same rhythm appears in the birth of children with neural tube defects (NTDs). In the northern hemisphere, both disorders thus show a conception peak in May-June and a trough around November-December. The senior author found the same May-June conception peak among left-handed American baseball players and the opposite effect (a November-December peak) among extreme right-handed players. A similar rhythm appeared with respect to characteristics related to artistic as opposed to scientific modes of thought. DISCUSSION: Schizophrenia has been proposed to involve a deficit in the establishment of lateral asymmetry, as does left-handedness. The artist-scientist dichotomy is also believed to involve cerebral dominance. Thus, the similarity of seasonal variation in month of conception between NTDs, schizophrenia, left-handedness, and artistic intuition suggests that these four conditions may share some factor affecting the cellular processes involved in both neural tube closure and asymmetry development during the early-fourth week, neural-fold stages of embryogenesis. We propose that maternal oxidant stress, which can rise with exposure to intense solar radiation, may interfere with both neural tube closure and asymmetry development. The June and December extremes of sunlight would thus explain the peak times of the seasonal fluctuations. Moreover, regardless of mechanisms, the parallel between the two conception rhythms suggests that the same periconceptional folate regimens found effective in preventing NTDs may also lower the risk of schizophrenia. This paper reviews some of the clinical and experimental evidence supporting this hypothesis.

Humans↗

Preliminary data on changes in neural tube defect prevalence rates after folic acid fortification in South America.

Several South American countries are fortifying wheat flour with folic acid. However, only Chile started in 2000 to add 2.2 mg/kg, providing 360 microg daily per capita, an acceptable dosage for preventing the occurrence of some neural tube defect (NTD) cases. ECLAMC (Spanish acronym for the Latin American Collaborative Study of Congenital Malformations) routinely monitoring birth defects in South America since 1976, surveyed the impact of this fortification. Data from 361,374 births occurred in 43 South American hospitals, distributed in five different countries, active throughout the 1999-2001 triennium, were selected from the ECLAMC network. Birth prevalence rates for three different congenital anomalies with similar expected prevalence rates, were surveyed by the Cumulative Sum Method (CUSUM) method. They were NTD, oral clefts (OC), and Down syndrome (DS). Expected values were derived from observations made in 1999, and CUSUM was applied to the consecutive series of 24 months covering years 2000 and 2001. Only one of three congenital anomaly types, NTDs, in only one of five sampled out countries, Chile, showed a significant decrease, of 31%, during the 2000-2001 biennium, corresponding to the birth of the periconceptionally fortified infants. The level of significance (P < 0.001) was reached in the 20th month after fortification started, corresponding to August 2001. This is the first observation of a significant decrease in the occurrence of NTD after folic acid food fortification in a population little influenced by confounders common in the developed world as pre-existing secular decreasing trends, and partially unregistered induced abortions.

Cleft Palate↗

Craniosynostosis in neural tube defects: a theory on its pathogenesis.

BACKGROUND: In most cases, craniosynostosis is a sporadic occurrence of unknown etiology. Efforts to ascertain the exact, cause of this deformation often fall to reveal its origin and pathogenetic mechanism. Some previous reports have described isolated instances of the association of neural tube defects (NTD) and craniosynostosis, but in none of them has a causal relationship been established to explain this coincidence, apart from a fortuitous sequence of congenital defects. METHODS: We have reviewed the clinical records of 40 patients diagnosed with craniosynostosis who were studied at our hospital over a 22-year period, for the purpose of determining the possible etiologies of this cranial deformation. RESULTS: We found that three children with unilateral coronal synostosis had associated NTD-an incidence of 7.5%. Two children had cephaloceles and the third harbored a lumbosacral myelomeningocele. In these three cases, the craniosynostosis was noted immediately after birth and before the development or treatment of hydrocephalus. CONCLUSION: We think that there must be an alternative explanation for the association of craniosynostosis and NTD other than overdrained hydrocephalus or chance association. We advance the hypothesis that in these cases the cause of the premature coronal synostosis was the lack of cerebral expansion. Since brain expansion and intracranial pulse pressure determine the growth and shape of the overlying cranial vault, the dampening effect of the malformation sac (myelomeningocele or cephalocele) on the intracranial pressure and on the pulse pressure may lead to close contact of the affected bones and to the premature closure of the coronal suture. The possibility of fetal head constraint because of diminished fetal activity due to the NTD as a contributory factor is also suggested.

Craniosynostoses↗

Amniotic fluid acetylcholinesterase measurement in the prenatal diagnosis of open neural tube defects. Second report of the Collaborative Acetylcholinesterase Study.

Seventeen centres from Australia, Britain, France, and the United States collaborated in a study to compare amniotic fluid acetylcholinesterase (AChE) determination by gel electrophoresis and amniotic fluid alpha-fetoprotein (AFP) measurement as diagnostic tests for open neural tube defects. The study was based on 32,642 women with singleton pregnancies (including 428 with open spina bifida and 238 with anencephaly) who had an amniocentesis at 13-24 weeks' gestation. The AChE test yielded a detection rate for open spina bifida of 99 per cent (95 per cent confidence interval 98-100 per cent), 98 per cent for anencephaly (95 per cent confidence interval 96-100 per cent), and a false-positive rate of 0.34 per cent (95 per cent confidence interval 0.28-0.40 per cent) excluding miscarriages, intrauterine death, and serious fetal abnormalities. The false-positive rate was 0.30 per cent among the 13 centres that used a specific AChE inhibitor in the test. Comparable rates for the AFP test were less favourable. (For example, the open spina bifida detection rate was 90 per cent and the false-positive rate was 0.46 per cent using the cut-off levels specified in the U.K. Collaborative AFP Study.) The AChE false-positive rate was lower in samples that were not bloodstained (0.16 per cent) than in those that were (2.4 per cent). It was higher in women who had an amniocentesis on account of a raised maternal serum AFP level (0.56 per cent) than in those who had one for other reasons (0.29 per cent). The best results were obtained by a combination of the two tests, an effective and economical policy being to perform the AFP measurement on all amniotic fluid samples and an AChE test on samples with AFP levels greater than or equal to 2.0 multiples of the normal median (about 5 per cent of all samples). Using this policy, the open spina bifida detection rate was 96 per cent and the false-positive rate was 0.14 per cent (0.06 per cent for samples that were not bloodstained and 1.2 per cent for those that were; 0.40 per cent for women with raised serum AFP levels and 0.09 per cent for other women). This policy offers a useful improvement to the prenatal diagnosis of open spina bifida.

Acetylcholinesterase↗

Chiari's description of cerebellar ectopy (1891). With a summary of Cleland's and Arnold's contributions and some early observations on neural-tube defects.

One hundred years ago, Chiari published his first paper on cerebellar ectopy. The contribution of his paper and those of Cleland (1883) and Arnold (1894) to the development of the knowledge of craniocervical abnormalities is discussed. Some early contributions (those of Tulp and Ollivier d'Angers) to the subject of neural-tube defects were also studied and it is concluded that Chiari's name should be connected with the different types of cerebellar ectopy.

Arnold-Chiari Malformation↗

The association of twinning and neural tube defects: studies in Los Angeles, California, and Norway.

Accurate, unbiased malformation rates in twins must be obtained unselectively from population-based studies that include livebirths and stillbirths after a thorough ascertainment of cases. This type of study was conducted in Los Angeles County, California, where 28 twins with a neural tube defect (NTD) were identified. The prevalence in twins (1.6/1,000) was significantly higher than in singletons (1.1/1,000). The study then was expanded to include population-based data from the Medical Birth Registry of Norway which has a comparable overall NTD prevalence (1.0/1,000) and twinning rate (2%). The combined material shows a higher prevalence of anencephaly and encephalocele but not of spina bifida in twins compared to singletons. The male/female ratios in total twin and singleton cases were comparable (0.8), but varied by specific defect. Like-sex twin females appeared at highest risk for NTD as well as for fetal death. This study supports theories which associate NTDs with monozygotic twins, either through developmental disruptions that cause susceptibility to environmental agents or through a common etiology. Furthermore, it suggests that twins and singletons differ in their response to etiologic factors for the development of NTDs and that the development of each type of NTD may be related to different factors.

California↗

PAX genes and human neural tube defects: an amino acid substitution in PAX1 in a patient with spina bifida.

From studies in the mouse and from the clinical and molecular analysis of patients with type 1 Waardenburg syndrome, particular members of the PAX gene family are suspected factors in the aetiology of human neural tube defects (NTD). To investigate the role of PAX1, PAX3, PAX7, and PAX9, allelic association studies were performed in 79 sporadic and 38 familial NTD patients from the Dutch population. Sequence variation was studied by SSC analysis of the paired domain regions of the PAX1, PAX7, and PAX9 genes and of the complete PAX3 gene. In one patient with spina bifida, a mutation in the PAX1 gene was detected changing the conserved amino acid Gln to His at position 42 in the paired domain of the protein. The mutation was inherited through the maternal line from the unaffected grandmother and was not detected in 300 controls. In the PAX3 gene, variation was detected at several sites including a Thr/Lys amino acid substitution in exon 6. All alleles were present among patients and controls in about the same frequencies. However, an increased frequency of the rare allele of a silent polymorphism in exon 2 was found in NTD patients, but no significant association was observed (p = 0.06). No sequence variation was observed in the paired domain of the PAX7 and PAX9 genes. Our findings so far do not support a major role of the PAX genes examined in the aetiology of NTD. However, the detection of a mutation in PAX1 suggests that, in principle, this gene can act as a risk factor for human NTD.

Amino Acid Sequence↗

Rudimentary meningocele: remnant of a neural tube defect?

BACKGROUND: Rudimentary meningocele, a malformation in which meningothelial elements are present in the skin and subcutaneous tissue, has been described in the past under a variety of different terms and has also been referred to as cutaneous meningioma. There has been debate as to whether rudimentary meningocele is an atretic form of meningocele or results from growth of meningeal cells displaced along cutaneous nerves OBJECTIVE: We reviewed the clinical, histological, and immunohistochemical characteristics of rudimentary meningocele in an attempt to assess the most likely pathologic mechanism for it. DESIGN: Retrospective study. SETTING: University hospitals. PATIENTS: Thirteen children with rudimentary meningocele. MAIN OUTCOME MEASURES: Medical records were reviewed and histopathologic examination as well as immunohistochemistry studies were performed for each case. A panel of immunoperoxidase reagents (EMA, CD31, CD34, CD57, S-100, and CAM 5.2) was used to assess lineage and to confirm the meningothelial nature of these lesions. RESULTS: Recent evidence indicating a multisite closure of the neural tube in humans suggests that classic meningocele and rudimentary meningocele are on a continuous spectrum. CONCLUSION: Rudimentary meningocele seems to be a remnant of a neural tube defect in which abnormal attachment of the developing neural tube to skin (comparable to that in classic meningocele) could explain the presence of ectopic meningeal tissue. In the majority of cases, no underlying bony defect or communication to the meninges could be detected. However, in light of the probable pathogenesis, imaging studies to exclude any communication to the central nervous system should precede any invasive evaluation or intervention.

Child↗

Clinical care of pregnant women with epilepsy: neural tube defects and folic acid supplementation.

Women with epilepsy (WWE) have a risk of bearing children with congenital malformations that is approximately twice that of the general population. Most antiepileptic drugs (AEDs) have been associated with such risk. Valproate and carbamazepine have been associated specifically with the development of neural tube defects (NTDs), especially spina bifida. Other factors may contribute to the risk, including concomitant diseases such as diabetes mellitus, occupational exposure to teratogens, excessive prepregnancy weight, and various nutrient deficiencies. In the general population, maternal folate deficiency, in particular, has been linked with the development of NTDs, and periconceptional folate supplementation with a reduction of risk. It is unclear whether folate supplementation has a comparable protective effect for WWE. Data concerning the risk for congenital malformations associated with the newer AEDs (gabapentin, felbamate, lamotrigine, levetiracetam, oxcarbazepine, tiagabine, topiramate, and zonisamide) are still limited. Several pregnancy registries for women taking AEDs have been established. Comprehensive postmarketing surveillance, regionally or nationally, might be the ideal method of monitoring medication safety, but government support for such an undertaking has for the most part been lacking. Despite uncertainty about the efficacy of periconceptional folate supplementation in WWE, these women should receive such supplementation at dosage levels recommended for the general population of women of childbearing age. Seizure control must not be neglected in a pregnant woman with epilepsy since seizures are associated with harm to the fetus as well as the mother. Risk may be minimized by using a single AED at the lowest effective dosage.

Abnormalities, Drug-Induced↗

Alpha fetoprotein screening and diagnosis of fetal open neural tube defects: the need for quality control.

A workshop, held in May, 1978, at the National Institute of Child Health and Human Development, considered the quality control of reagents and assays for measuring alpha fetoprotein (AFP) in maternal serum and amniotic fluid for the antenatal screening and diagnosis of open neural tube defects. The recommendations, published in detail elsewhere and summarized in this article, were based on what was known to be readily achievable and on estimates of the effect of assay performance on screening and diagnostic sensitivity and specificity. Main points considered included: (1) choice of units for AFP measurement and interpretation, (2) need for National AFP Reference Preparations and the need for a scientific panel to assess the adequacy of these reference materials, (3) information needed from reagent manufacturers, (4) criteria for assay performance, (5) biological sources of reagents, (6) need for laboratory and epidemiologic monitoring, and (7) need for a minimum assay workload.

Amniotic Fluid↗

Screening for neural-tube defects and maternal anxiety.

Anxiety levels were studied in 176 women with raised serum alpha-fetoprotein levels at 16-18 weeks gestation, at the time they attended a central assessment clinic, and again 2-3 weeks later in those not found to have a fetus with a neural-tube defect. Methods of imparting information about the serum screening tests and the manner in which a normal amniotic fluid result was conveyed to the patient were also studied. Overall, women attending the clinic for further assessment were extremely anxious, irrespective of the source of their information. Anxiety scores 2-3 weeks after testing were greatly influenced by whether the patient had been given a definite normal result or whether she was told to assume that the result was normal if she did not hear from the clinic. Patients who, after reassessment, did not require amniocentesis had some residual anxiety in spite of verbal reassurance.

Amniocentesis↗

The use of multivariate discriminant analysis in the antenatal detection of fetal neural tube defects.

Early second trimester amniotic fluid is classified by stepwise discriminant analysis involving the computer program BMDP77, based upon biochemical analyses for alpha-fetoprotein and eight other easily assayed variables. The outcome of about 800 pregnancies has been predicted on this basis, over 80 of which were associated with fetal neural tube defects. Classification is shown to be more reliable than using alpha-fetoprotein and gestational age alone. Although in practice this approach has now been superceded by the introduction of the analysis of acetylcholine-esterase isoenzyme activity in amniotic fluid, the results demonstrate a successful application of discriminant analysis to medical diagnosis.

Amniocentesis↗

Amniotic fluid test for the diagnosis of neural tube defects.

Alpha-fetoprotein and acetylcholinesterase were assayed in 374 amniotic fluids from normal pregnancies, at 9-15 weeks of gestation. We have investigated the correlations with the gestational age and have established our cutoff levels for these biochemical markers. We also report the values, that we have obtained in two cases of neural tube defects (NTD) and in several chromosomal aberrations. For early prenatal diagnosis of NTD, we wide to point out the importance of the contemporary determination of the two analytes and of the ultrasonographic investigation and biometry.

Acetylcholinesterase↗

Brief clinical report: neural tube defects in dup(11q).

We describe clinically and cytogenetically a fetus with multiple congenital anomalies and partial dup(11q) born to a phenotypically normal mother with a 3:1 translocation. Fetal anomalies included complete cleft of lip and palate, small penis, myelomenigocele, and abnormal palmar creases. We think chromosome analysis should be performed when neural tube defects are observed in otherwise dysmorphic neonates, stillbirths, and abortuses.

Abnormalities, Multiple↗

Spondylocostal dysplasia and neural tube defects.

Spondylocostal dysplasia (Jarcho-Levin syndrome) comprises multiple malformations of the vertebrae and ribs coupled with a characteristic clinical picture of short neck, scoliosis, short trunk, and deformity of the rib cage. We describe a patient with the syndrome who also had spina bifida and diastematomyelia. We surmise that this association is not coincidental. Additional evidence is needed to support the hypothesis that spondylocostal dysplasia and neural tube defects are aetiologically related.

Dysostoses↗

Trend in prevalence of neural tube defects in Quebec.

BACKGROUND: In Canada, the first recommendations on the use of folic acid (FA) supplements by women planning a pregnancy or capable of becoming pregnant were issued in 1993. In 1998, fortification of flour with FA became mandatory. The objective of this study was to assess the impact of these measures on the prevalence of neural tube defects (NTDs) in the province of Quebec. METHODS: The study population included stillbirths, live births, and elective terminations for fetal malformations that were reported in 1992-2000 for women residing in the province of Quebec. NTD cases were identified from stillbirth certificates and hospital discharge summaries. RESULTS: There was a marked decrease in the total NTD rate after 1997. The average NTD rate was 1.89 per 1000 total births during the period of 1992-1997, and 1.28 per 1000 in 1998-2000, a 32% reduction (p < 0.001). CONCLUSIONS: Fortification of flour, which began in early 1997 and gradually became widespread, is a very plausible explanation for the timing, shape, and magnitude of the decrease in NTD prevalence observed in Quebec and other Canadian provinces. An increase in FA supplement use may have played only a minor role. Birth Defects Research (Part A) 67:000-000, 2003.

Dietary Supplements↗

Folic acid awareness and use among women with a history of a neural tube defect pregnancy--Texas, 2000-2001.

The use of folic acid is a critical component in preventing birth defects. Health-care providers should take advantage of all health-care visits to counsel not only women at high risk (i.e., those with a history of having an infant with a neural tube defect [NTD]) but all women regarding the importance of folic acid use. A study conducted in Texas confirmed that white and Hispanic mothers were equally likely to recall receiving postpartum advice to use folic acid; however, Hispanic women were much less likely to use folic acid, compared with white women. This report covers data from May 2000 through November 2001. A study was conducted in Texas to determine whether women at high risk recall and follow recommendations to use folic acid. The study included 195 women at high risk and 223 control mothers who gave birth to infants without birth defects. These women participated in a telephone interview for a population-based case-control study of NTDs. Approximately 56.4% (110 of 195) of mothers who had infants affected by an NTD recalled receiving postpartum advice to use folic acid, compared with 25.6% (57 of 223) of control mothers (p < 0.01). Among nonpregnant case mothers, 54 (32.7%) of 165 reported regular use of supplements containing folic acid, and 53 (25.2%) of 210 nonpregnant control mothers reported this behavior (p = 0.11). Among case mothers, use of folic acid was significantly higher for whites (64.7%) versus Hispanics (16.5%) (p < 0.001); for women with some college education (57.1%) versus no college education (20.2%; p < 0.001); for women who were trying to get pregnant (66.7%) versus those using birth control (38.3%) or reporting using no contraceptive method (18.8%) (p = 0.001); and for women who reported receiving advice to use folic acid (40.9%) versus those who did not (22.2%; p = 0.01). Findings from this study support the need to implement NTD recurrence prevention activities in Texas. Data also identify a need for educational strategies in Texas that target Hispanic women at high risk, especially those who primarily speak Spanish. Further efforts should be made to determine why Hispanic women have low rates of folic acid use (e.g., the cost of vitamins and language and cultural barriers). On the basis of a review of research and current practice, recommendations developed by the Public Health Service include 1) women at risk for a recurrent NTD-affected pregnancy should take 0.4 mg of folic acidper day; and 2) if a woman at high risk is planning a pregnancy, she should consult her physician regarding taking the higher dose of 4.0 mg per day.

Adult↗

Decline of neural tube defects cases after a folic acid campaign in Nuevo León, México.

BACKGROUND: Nuevo León is a state in northeastern Mexico, near the border of Texas. Mean mortality rate from 1996-98 due to anencephaly cases was 0.6/1,000. In 1999 a surveillance program for the registry and prevention of neural tube defects (NTD) cases was initiated. METHODS: Cases were obtained from hospitals and OB-GYN clinics by immediate notification, death certificates, or fetal death registries. Only isolated cases of NTD were included. In August 1999 a folic acid campaign was initiated with the free distribution of the vitamin to low-income women with a recommendation to take a 5.0-mg pill once a week. Number of cases and rates from 1999 to 2001 were compared (chi(2) test). RESULTS: After 2 years there has been a significant reduction in the number of cases and rates. In 1999 there were 95 NTD cases and in the years 2000 and 2001 there were only 59 and 55 respectively (P < 0.001). NTD rate decreased from 1.04/1,000 in 1999 to 0.58/1,000 in 2001. Anencephaly and spina bifida rates decreased from 0.55/1,000 to 0.29/1,000 and from 0.47/1,000 to 0.22/1,000 respectively, from 1999-2001. Decrease of female cases was higher than male cases for both phenotypes. CONCLUSION: After 2 years there was a 50% decrease in the incidence of anencephaly and spina bifida cases with a significant reduction of infant mortality and disability. These results encourage us to propose the use of a single tablet of 5.0-mg of folic acid per week as an alternative to supplementation on a daily basis.

Anencephaly↗