Study Of Neural Tube Defects Research Articles

Multigeneration maternal transmission in Italian families with neural tube defects.

Periconceptional vitamin supplementation with folate prevents about three-quarters of expected cases of neural tube defects (NTDs) in clinical trials. However, vitamin action may be regulated at the level of the gene, and individual susceptibility to environmental agents, including dietary components, also may be under genetic control. We investigated the presence of familial factors in a retrospective case control study of neural tube defects in Genoa, Italy. Cases included all patients treated at a single pediatric neurosurgical service. Controls matched on age and sex came from the same hospital. We found strong evidence for the contribution of genetic factors in this study. There was an excess risk of 14 for the occurrence of NTDs in first-degree relatives compared to controls (P < .0005). There was no difference in sex ratio in any group of relatives, but maternal grandparents of children with a high spinal lesion had 14% fewer off-spring than paternal grandparents (P < .005), possibly because of excess miscarriages. Our study is the first to show complex patterns of inheritance in spina bifida families affecting three generation in one clinical subgroup and preferentially on the mother's side. These results support a role for genomic imprinting and highlight the value of multidisciplinary epidemiologic and clinical studies that include multiple generations. New studies incorporating dietary and genetic approaches will help clarify and extend these findings.

Hispanic origin and neural tube defects in Houston/Harris County, Texas. II. Risk factors.

Several investigators have reported Hispanics to be at elevated risk for neural tube defects (anencephaly and spina bifida). Factors contributing to this risk have not been established. The authors conducted a case-control study of neural tube defects (NTDs) among births occurring in Harris County, Texas, from April 1, 1989, through December 31, 1991. Through the use of multiple ascertainment methods, 59 cases of anencephaly and 32 cases of spina bifida were detected. Controls (n = 451) were sampled for the same time period from Harris County vital records. Regardless of how Hispanic ethnicity was classified, having a Hispanic parent was a risk factor for both anencepahly and spina bifida. The primary etiologic question was whether increased NTD risk in Hispanics is explained by maternal diabetes or by other factors (e.g., maternal birthplace, prenatal care, reproductive history, age, socioeconomic status). Mexico-born Hispanics were no more likely than Texas-born Hispanics to deliver a fetus or infant with an NTD. Having a Hispanic mother was a risk factor for anencephaly among infants born to women with early prenatal care (odds ratio (OR) = 4.54, 95% confidence interval (CI) 2.21-9.40) but not for those born to latecomers. Earlier prenatal care seemed "protective" for non-Hispanics (OR = 0.18, 95% CI 0.06-0.65) but not for Hispanics. After simultaneous adjustment for eight variables in multivariate analysis, having a Hispanic (versus non-Hispanic) mother remained a strong risk factor for both anencephaly (OR = 2.58, 95% CI 1.19-5.61) and spina bifida (OR = 3.71, 95% CI 1.48-9.31). Any previous pregnancy termination/fetal loss was also associated with anencephaly in a final logistic regression model (OR = 2.48, 95% CI 1.20-5.10), and having a teenage mother (aged < 20 years) approached significance (OR = 2.21, 95% CI 0.92-5.31). "Hispanic mother" was the only study variable significantly associated with spina bifida in multivariate analysis. Results for diabetes suggested no association with anencephaly (OR = 1.24, 95% CI 0.25-6.17). An increased risk of NTDs among Hispanics remained after controlling for other factors. For anencephaly, this risk might be partially explained by economic and cultural differences between Hispanics and non-Hispanics, and the effect of these factors on rates of prenatal diagnosis and elective pregnancy termination.

Fallacies of international and national comparisons of disease occurrence in the epidemiology of neural tube defects

Despite extensive research, little progress has been made in elucidating the etiologies of anencephalus and spina bifida. International and national distributions of disease occurrence have often been used as a basis for generating etiological hypotheses (e.g., potato blight, tea consumption, and zinc deficiency hypotheses). However, few of the epidemiological studies of neural tube defects (NTDs) have been conducted with scientific rigor in design, and most are of dubious validity, often with low precision in the estimates. This paper shows that the accepted geographic patterns of NTDs may be attributable to variations in the validity of studies used to describe these patterns. The nonuniformity in the duration and diligence of case ascertainment, the lack of a standardized nomenclature and classification, and the definition of the denominator remain principal problems in evaluating the epidemiology of NTDs. For example, the distinction between incidence and prevalence is not always made, and there is no consistency in the placement of the gestational boundary between late fetal deaths and spontaneous abortions. Findings are compared from studies conducted at different times, without due regard to the effect of secular trends, and using studies that have varying levels of case ascertainment. In etiological research, it is important to perform studies that are accurate and precise, but the literature used to define the spatial distribution of NTDs has often been accepted without due regard to the effect of these factors.

Genetic analysis of the cause of exencephaly in the SELH/Bc mouse stock.

A new mouse stock, SELH/Bc, having a high liability to exencephaly has been developed. About 17% of SELH fetuses are exencephalic. The genetic cause of this exencephaly was investigated in a cross to a normal related ICR/Bc strain and in subsequent classical genetic crosses (F2, first and second backcrosses). The data were compared with a number of genetic models, including that of a single recessive mutation with 17% penetrance. The data did not fit single-locus inheritance. The expectations from the multifactorial threshold model based on an underlying quantitative liability trait with additive inheritance were found to fit the data very well. The number of loci involved was estimated to be about two or three. About 70% of exencephalic SELH fetuses are female, and there is no overall deficiency of males. The relatively higher risk in females was constant across the genetic backgrounds in the experiment. In summary, the liability to exencephaly in SELH mice appears to be a multifactorial threshold trait, and it therefore resembles human neural tube defects in type of genetic etiology. SELH therefore may be a valuable animal model in the study of neural tube defects.

Epidemiological studies of neural tube defects in Newfoundland.

A 9-year survey of neural tube defects in Newfoundland showed (1) evidence for secular variation, with a peak in 1980, but no general downward trend as seen in some other populations; (2) significant geographic variation which did not correlate with hardness or nitrate content of the lake water; (3) a tendency for the proportion of females among anencephalic births to increase with increasing frequency of anencephaly among geographic regions. This supports previous evidence for a female-specific contribution to the causes of increased liability to neural tube defect.

A cohort study of neural tube defects (NTD) in Denmark covering the first seven years of life.

In the County of Fyn, Denmark, which is a well-delimited region comprising a 10% representative sample of the total population, ten complete one year cohorts of newborn were scrutinized for neural tube defects (NTD). Among 66,000 births, 71 cases with NTD were observed. The total prevalence at birth was 1.08/1,000; 0.29 for anencephaly; 0.20 for encephalocele, and 0.59 for spina bifida (SB). This is at the same level as in other Scandinavian countries. Considering only neonates born alive, 57% of the total survived until the age of 7 years, disregarding anencephaly, but only 4 of 18 SB cases and 6 of 11 encephalocele cases had no handicaps at age 7. On the average, SB patients spent 9% of their life before the age of 7 years in hospitals and encephaloceles 2%. The SB cases occupied 25 times more beds per year than the comparable age group in general and many were likely to need continued medical and social care.

Studies in neural tube defects. I. Epidemiologic and etiologic aspects.

In the NIH Collaborative Perinatal Project, a prospective study of over 53,000 pregnant women and their offspring, 71 single-born children (13.33/10,000) were found to have a non-syndromal neural tube defect (NTD). A family history was present in only one case. The group of individuals with NTD was compared to a group of 400 randomly selected non-malformed control infants. Of over 50 maternal factors studied the following showed significant association with NTD in the offspring: diabetes mellitus; organic heart disease; lung disease; and diuretic, antihistamine, and sulfonamide use. The interval between the termination of the immediately previous pregnancy and the start of the proband pregnancy was significantly shorter in mothers of NTD children than in mothers of control infants. The risk for NTD was also significantly increased if the immediately previous pregnancy was a spontaneous abortion. There was no increased risk for NTDs among sibs of children with major malformations such as tracheo-esophageal "dysraphism," cleft lip/palate, or renal agenesis. NTDs are apparently etiologically heterogeneous.

Studies in neural tube defects. II. Pathologic findings in a prospectively collected series of anencephalics.

This report presents the pathologic anatomy of a prospectively collected series of 36 anencephalic infants. This series provides an opportunity to investigate the epidemiology of organ system pathology in anencephaly (AN) as well as other facets of its natural history. AN infants had a mean gestational age 2.5 weeks younger than normal controls, though birthweight was normal for gestational age. Nearly 1/3 of the liveborn infants with AN died within 15 minutes, 2/3 within 3 hours; 3 AN infants survived to 48 hours. Details and discussions of the pathologic findings and their physiologic significance are presented. Regarding those AN infants who received detailed neurologic examinations, correlations are made between the brain pathology and neurologic function prior to death.

A chromosome marker for the early detection of mouse embryos carrying the neural tube defect mutation splotch.

A major problem in the study of neural tube defects caused by the splotch (Sp) gene in the mouse has been the identification of gene carriers or potentially affected embryos at an early stage of development, since the gene's effects become visible only late in gestation or after birth. To aid in the identification of Sp carriers, we have developed a technique using a Robertsonian translocation as a marker for this gene. The accuracy of identification is reduced by crossing-over between the Sp locus and the centromere but, because of crossover suppression in the particular cross used, there was only 23.2% recombination compared with the known map distance of 36%. Paternal age had no effect on the frequency of recombination, but individual males differed significantly in the degree of crossover suppression.

Epidemiology of neural tube defects in Germany.

A survey is made of the epidemiologic studies of neural tube defects (NTD) in Germany. A temporary increase is noted in the prevalence of NTD at birth for the time during and shortly after the Second World War, followed by a downward trend thereafter. Thus an earlier observation of Lenz (1965) could be confirmed. Falling rates of NTD were also reported from various other countries in recent years. No convincing etiological explanation is available so far. The current prevalence of NTD at birth can be estimated for Germany to be about 1.0-1.5 per thousand newborns with about an even distribution to anencephalus and spina bifida.

A correlational study of neural tube defects and infectious diseases

This paper presents a study of the relationship between levels of community-reportedinfectious diseases (measles, rubella, influenza, mumps, scarlet fever, hepatitis A, and salmonella) and rates of neural tube defects (anencephalus and spina bifida) in Los Angeles County during 1968–77. Cases of anencephalus and spina bifida were ascertained from vital records, and rates of the infectious diseases under study were obtained from county Communicable Disease reports. No statistically significant correlation was observed between the quarterly trends of infectious diseases and neural tube defects over the study period. No relationships were observed between the seasonal patterns of neural tube defects and the diseases. Using periods of elevated disease activity to determine hypothetical high- and low-risk periods for conceiving infants with these defects, none of the rate ratios was significantly elevated above unity for any of the infectious diseases under study. Because of limitations in study design, accuracy of case identification, and accuracy of disease reporting, our results cannot be interpreted as disproving a role for these infectious diseases in the etiology of neural tube defects. Nevertheless, our results do indicate that such associations as may exist are not strong enough to be reflected in community health data.

An epidemiologic study of neural tube defects in Los Angeles County II. Etiologic factors in an area with low prevalence at birth.

Epidemiologic characteristics of neural tube defect (NTD) births occurring in Los Angeles County, California, residents during the period 1966-1972 are presented. The prevalence at birth was 0.52/1000 births for anencephalus, 0.51/1000 for spina bifida, and 0.08/1000 for encephalocele, rates considered to be low for a predominantly white population. We hypothesized that environmental (nongenetic) factors are of less etiologic importance in a low-prevalence population than in areas or time periods with high prevalence. We tested that hypothesis by examining epidemiologic characteristics of NTDs in Los Angeles County and comparing them with high-prevalence populations. The data did not support a major etiologic role for environmental factors: (1) no significant differences between rates by month of birth or conception; (2) no significant association with maternal age or parity for anencephalus; for spina bifida a significant maternal age effect (P less than 0.01) and for encephalocele a parity effect (P less than 0.02); and (3) no significant relationship with father's occupational class for either anencephalus or encephalocele but a marginally significant (P less than 0.05) inverse association for spina bifida when a statistic based on ordinal relationships was used. Findings supporting the importance of genetic factors in etiology included: (1) a high percentage of males; (2) a higher twin concordance rate than in high-prevalence populations; and (3) an anencephalus rate among blacks comparable with rates for blacks in other United States populations. Our findings in conjunction with those from other areas and times of low prevalence suggest environmental factors play a relatively insignificant role in the etiology of NTDs in such populations.

Etiologic heterogeneity of neural tube defects: clues from epidemiology.

The epidemiology of neural tube defects was reviewed, using data from two birth defects surveillance systems: the nationwide Birth Defects Monitoring Program and the Metropolitan Atlanta Congenital Defects Program, for 1970-1978 and 1968-1979, respectively. After excluding cases with recognized causes, neural tube defects were divided into two major groups: "singles" and "multiples," depending on the presence of associated major defects. Only singles, which accounted for the majority of cases, were shown to have the well-known epidemiologic characteristics of neural tube defects: marked predominance of females and whites, geographic variation with an east-to-west gradient, and decreasing rates over time. On the other hand, multiples had no excess of females and occurred less predominantly in whites; moreover, their rates showed no geographic variation and little or no downward trends over time. The presence of associated defects indicates that neural tube defects are epidemiologically and probably etiologically heterogeneous. It is suggested that analytic studies of neural tube defects may be more rewarding if they try to identify different risk factors associated with various subgroups. This approach to the study of birth defects may provide better clues to their etiology and pathogenesis.

Epidemiological study of neural tube defects in human embryos

Epidemiological study of neural tube defects in human embryos