PEDIATRICS Vol. 118 No. 3 September 2006, pp. 916-923 (doi:10.1542/10.1542/peds.2005-1739)
ARTICLE |
Are Encephaloceles Neural Tube Defects?
National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, Georgia
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONREFERENCES |
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OBJECTIVE. Encephalocele is classified as a neural tube defect, but questions have been raised regarding whether its epidemiological characteristics are similar to those of other neural tube defects.
DESIGN. We compared characteristics of temporal trends in, and the impact of folic acid grain fortification on, the prevalence of encephalocele, spina bifida, and anencephaly using data from the Metropolitan Atlanta Congenital Defects Program, a population-based birth defects surveillance system. Prevalences of encephalocele, spina bifida, and anencephaly were compared by maternal age, gender, race, birth weight, ascertainment period (1968–1981, 1982–1993, or 1994–2002), and fortification period (1994–1996 [prefortification] and 1998–2002 [postfortification]) using prevalence ratios with 95% confidence intervals. Temporal trends were assessed using Poisson and negative binomial regression models.
RESULTS. Prevalence rates of encephalocele (n = 167), spina bifida (n = 650), and anencephaly (n = 431) were 1.4, 5.5, and 3.7 per 10 000 live births, respectively. Encephalocele was similar to anencephaly in showing an increased prevalence among girls and multiple gestation pregnancies and to spina bifida and anencephaly in an annual prevalence decrease between 1968 and 2002 (–1.2% for encephalocele, –4.2% for spina bifida, and –3.6% for anencephaly). With fortification, prevalence decreased for spina bifida but not significantly for encephalocele or anencephaly.
CONCLUSIONS. Encephalocele shows more similarities to spina bifida or anencephaly than it shows differences with respect to characteristics, temporal trend, and impact of fortification. Additional studies should be done to explore the etiologic heterogeneity of encephalocele using better markers of folate status and a wider range of risk factors.
Key Words: encephalocele • neural tube defects • spina bifida • anencephaly • folic acid
Abbreviations: NTD—neural tube defect • SB—spina bifida • MACDP—Metropolitan Atlanta Congenital Defects Program • PR—prevalence ratio • CI—confidence interval
Encephalocele refers to a group of rare congenital anomalies of the central nervous system where brain tissue protrudes from a defect in the skull. Encephalocele can occur in isolation, as well as with other unrelated congenital defects or as part of a well-described syndrome.1–3 Although improvements in surgical technique have improved outcomes in some types of encephalocele, overall morbidity and mortality remain high.4,5
Although encephalocele is typically classified as a neural tube defect (NTD), its underlying mechanism may differ from that of spina bifida (SB) and anencephaly. Two embryologic models of neural tube development exist: one involving a bidirectional "zipper"-like closure and the other involving multiple closure sites.6–8 Although the multisite closure model may help explain the variation in the anatomic location of the defect in the skull found in patients with encephalocele, this model may not account for other genetic and embryologic discrepancies between SB and anencephaly as compared with encephalocele. Genetic studies examining probands with nonsyndromal NTDs found that sibling concordance and prevalence of unrelated congenital anomalies differed between SB and anencephaly as compared with encephalocele.9 Also, findings of epithelialization and the absence of dysraphic brain tissue in those with encephalocele challenge the hypothesis that the mechanism of encephalocele is the same as other NTDs.10–14
If the mechanism of origin for encephalocele is different from that of SB and anencephaly, it is possible that risk factors might differ between these lesions, and that the prevalence of encephalocele might not have been affected as much as SB or anencephaly by folic acid fortification. For instance, to date, whether folic acid has a similar effect on preventing encephalocele as it does on preventing SB or anencephaly is unclear.15,16 In some populations, the prevalence of encephalocele has not significantly declined even after increased maternal intake of folic acid.17–19
If the mechanism of action of encephalocele as an NTD differs from that of SB and anencephaly, we hypothesize that encephalocele and other NTDs may differ in some epidemiological characteristics. In this study, we compared the descriptive epidemiology, prevalence trends over time, and impact of folic acid fortification on the prevalences of encephalocele, SB, and anencephaly in metropolitan Atlanta from 1968 to 2002.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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Data Sources
We identified infants with encephalocele and those with SB or anencephaly from the Metropolitan Atlanta Congenital Defects Program (MACDP) from 1968 through 2002. The MACDP is an active, population-based birth defects surveillance system among residents of the 5 central counties in Atlanta. This system was started in October 1967 and has currently collected information for >40000 infants and fetuses with birth defects among >1 million live births. Trained abstractors visit area birth and pediatric hospitals and genetic laboratories to review the medical charts of infants and fetuses of
20 weeks' gestation with birth defects. Information about live-born infants with birth defects is updated until the age of 6 years. Denominator data on the number of live births to residents of the 5 counties are obtained from vital records of the Georgia Department of Human Resources. In 1994, MACDP abstractors began to visit the outpatient offices of perinatologists and maternal fetal medicine departments in Atlanta to identify defects that were diagnosed prenatally. Affected pregnancies that did not deliver in a hospital and for which the outcome was not documented in the prenatal record were assumed to have been electively terminated. Additional details regarding MACDP are published elsewhere.20,21
Case Definition
Modified 6-digit codes 740.000 to 742.999 from International Classification of Diseases, Ninth Revision codes 742.0, 741, and 740.0 were used to identify infants and fetuses in the MACDP data with encephalocele, SB, and anencephaly, respectively. Infants and fetuses with an unconfirmed diagnosis were excluded from the analysis. In addition, those with the following diagnoses were also excluded: amniotic bands, clinical syndromes such as Meckel-Gruber, chromosomal abnormalities, craniorachischisis, iniencephaly, lipomyelomeningocele, conjoined twins, acardiac twin, and any combination of encephalocele, SB, or anencephaly occurring in the same infant.
Characteristics of Encephalocele
We classified infants with encephalocele by the level of anatomic lesion (occipital, parietal, frontal, or not stated) and the presence or absence of multiple unrelated defects (multiple versus isolated).22 The classification of defects in each infant was performed according to guidelines set forth previously23 and verified by a clinician. We compared infants with isolated encephalocele and those with encephalocele and multiple unrelated defects by infant gender (male or female), maternal age (<15–19, 20–34, or 35), race (white, black, or other), birth weight (
2499, 2500–3499, or 3500 g), gestational age (36, 37–42, or 43 weeks), and plurality (singleton or multiple). In our comparison by birth weight, we included only live births, and for our comparison by gestational age, we included live and stillbirths. Because the black race category was first included on vital records in 1973, we limited our analysis by race to the years 1973–2002. Because vital records data were missing for birth weight from 1974–1977 and for gestational age from 1973–1987, we estimated these data from the distribution of birth weight and gestational age for the 4 or 5 years immediately before and after the missing data, respectively.
Comparison of Encephalocele With Anencephaly and SB
Because prenatal diagnosis in Atlanta was introduced before the inclusion of outpatient prenatal diagnostic sources in the MACDP methods, we divided the data into 4 ascertainment periods for trend analysis: (1) the overall time period (1968–2002); (2) the period before prenatal diagnosis of NTDs was widely used in Atlanta (1968–1981); (3) the period when outpatient prenatal diagnosis began to be used in Atlanta but during which MACDP included only hospital sources (1982–1993); and (4) the period when MACDP included outpatient prenatal diagnostic sources (1994–2002).
We compared infants with encephalocele, SB, or anencephaly separately by demographic and clinical characteristics, limiting our analysis by race to the years 1973–2002 and excluding stillbirths from the comparison by birth weight and elective terminations from the comparison by gestational age. We also compared the prevalence of encephalocele, SB, and anencephaly by ascertainment period and before (1994–1996) and after (1999–2002) fortification of the US grain supply with folic acid in 1998.
Statistical Analyses
Prevalence rates between categories of a variable were compared using prevalence ratios (PRs) and 95% confidence intervals (CI) using SABER v.1.96 (Centers for Disease Control and Prevention, Atlanta, GA). If any cell count was <5, LogExact (Cytel Corp, Cambridge, MA) was used to estimate the PR and 95% CIs. Poisson and negative binomial regression analyses were conducted to test for trends in prevalence rates in each ascertainment period (1968–1981, 1982–1993, 1994–2002, and 1968–2002) using SAS 9.1 (SAS Institute, Cary, NC). Regression model selection was based on significance of the goodness-of-fit test and deviance for each model.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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We found 167 infants and fetuses in Atlanta meeting the case definition of encephalocele. Of these, 117 (70.1%) were live births, 23 (13.8%) were stillbirths, and 24 (14.4%) were pregnancies electively terminated after prenatal diagnosis. Seventy-six percent of the encephalocele cases were isolated, and 24.6% had multiple unrelated defects. Isolated, occipital lesions were the most frequent (Table 1).
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Stratification of encephalocele cases and rates by clinical and demographic characteristics showed that 69 (41.3%) of the infants with encephalocele were boys and 89 (53.3%) were girls, with girls having a higher prevalence rate (Table 2). Seventy-five (44.9%) of the infants and fetuses with encephalocele were white, 60 (35.9%) were black, and 11 (6.6%) were of "other" races, with higher rates found in blacks than in whites. Compared with those weighing 2500 to 3499 g, infants weighing
2499 g had higher prevalence rates, and those weighing 3500 g had lower prevalence rates. Higher rates were found in infants born at 36 weeks of gestation, and lower prevalence rates were found in those >40 weeks of gestation, although not statistically significant, as compared with term infants. Infants and fetuses with isolated encephalocele and those with multiple unrelated defects had similar characteristics. The prevalence of encephalocele did not vary significantly with maternal age and plurality. Although decreases in prevalence occurred in the latter ascertainment and postfortification periods, these decreases were not statistically significant.
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Examining prevalence rates of encephalocele, SB, and anencephaly, we found that encephalocele and anencephaly both had increased prevalence rates among girls and multiple-gestation pregnancies as compared with boys and singletons, respectively (Table 3). Encephalocele, SB, and anencephaly all had increased prevalence rates among the "other" race category as compared with whites, low birth-weight infants as compared with those weighing 2500 to 3499 g and preterm infants as compared with those born between 37 and 40 weeks' gestational age. Decreased prevalence rates were found for encephalocele, SB, and anencephaly among those weighing
3500 g as compared with those weighing 2500 to 3499 g and with fortification. Encephalocele differed from SB and anencephaly in showing similar prevalence among blacks and whites, whereas SB and anencephaly showed significantly lower prevalence rates among blacks than among whites. Compared with the period 1968–1981, subsequent ascertainment periods showed significantly lower prevalence rates for SB and anencephaly but not for encephalocele. Maternal age was not significantly associated with any defect.
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During the period 1968–2002, the overall prevalence of encephalocele, SB, and anencephaly decreased (Fig 1), but this decrease was significant only for SB and anencephaly. When analyzed by time period (1968–1981, 1982–1993, and 1994–2002), there were decreases in prevalence rates in most time periods for all of the defects except in 1968–1981 for encephalocele, which had an increase in prevalence rate (Table 4). A significant decrease in prevalence rate over time was found in 1982–1993 for encephalocele, 1968–1981 and 1982–1993 for SB, and 1968–1981 for anencephaly.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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Between 1968 and 2002, the prevalence of encephalocele in Atlanta was 1.4 per 10 000 live births, which is similar to the national reported prevalence.8,15,24 However, the proportion of occipital lesions in Atlanta (60%) was lower than that cited in most published reports (
75%).22,25 This lower proportion of occipital lesions may be attributable in part to the fact that some of the infants with encephalocele born in the earliest years did not have information regarding anatomic location of lesion and were classified as "not otherwise specified." Our finding that 24.6% of infants with encephalocele had multiple unrelated congenital anomalies was also lower than previous estimates of 32.5% and 40.2%7,15,19,26 reflecting, in part, our exclusion of infants with amniotic bands, clinical syndromes such as Meckel-Gruber, and any combination of encephalocele, SB, or anencephaly occurring in the same infant. Regional differences in study populations may have also contributed to this difference. The sociodemographic and clinical characteristics of infants and fetuses with isolated lesions and those with multiple unrelated defects were similar. We excluded infants and fetuses with any combination of encephalocele, SB, and anencephaly occurring in the same infant to examine possible risk factors for encephalocele separately from the other defects. Of interest is the relatively high proportion of infants and fetuses with encephalocele and SB and/or anencephaly (6.5%), which might be consistent with a common problem with neural tube closure.27
Encephalocele shows more similarities to SB and/or anencephaly than differences with respect to sociodemographic characteristics. Encephalocele was similar to anencephaly in increased prevalence among girls, young mothers, and multiple-gestation pregnancies. Increased prevalence among girls has been documented previously.15,28–30 Encephalocele was similar to SB and anencephaly in increased prevalence among the "other" race category versus whites, low birth-weight infants, and preterm infants and in decreased prevalence since 1968 and with fortification. Although we could not subdivide the "other" race group into subgroups such as Hispanic and Asian, our finding of an excess rate of encephalocele, SB, and anencephaly among "other" race category as compared with whites is similar to previous findings.29–31 The increased rate of encephalocele among low birth-weight and preterm infants has been described in previous studies17,32 and is commonly seen in other birth defects.33,34 Also, encephalocele differs from SB and anencephaly in showing a higher prevalence among black infants than among whites.
Encephalocele, SB, and anencephaly are also similar in temporal trends and impact of fortification on prevalence rates. Encephalocele, SB, and anencephaly showed a decreasing prevalence trend in the 1968–2002 ascertainment period. The lack of a statistically significant overall decline for encephalocele may be attributable, in part, to the extremely low prevalence of encephalocele at baseline and the small number of cases of encephalocele observed over time. Encephalocele, SB, and anencephaly also had lower prevalence rates in the postfortification period than in the prefortification period, but this decrease was only significant for SB. Although postfortification decreases in prevalence rates have been reported for SB and anencephaly,21 we could not find reports of postfortification prevalence rates for encephalocele. Although these decreases are consistent with effects from folic acid fortification, other possible factors that could help explain these declines include an underlying downward temporal trend combined with an artificial increase in prevalence because of an increase in case ascertainment with incorporation of perinatal centers as sources of data beginning in 1994. We do not think, however, that this decrease was because of an increase in elective terminations, because the frequency of termination was similar for prefortification and postfortification periods. Studies using individual measures of folic acid intake would probably help clarify the reason(s) for the decrease in prevalence over time.
This study has several strengths. We describe the epidemiology of encephalocele among births in a defined population, in Atlanta, over 34 years using a large, population-based surveillance system for birth defects. One advantage of this surveillance system is that it provides sufficient, reliable clinical information to allow for the classification of cases by the presence of other unrelated defects. In addition, we were able to obtain population-based prevalence estimates and perform stratified analyses by specific clinical and demographic characteristics. Because MACDP has existed for >30 years, we were able to look for time trends over extended periods, as well as within specific time periods of interest, which has not been reported before for encephalocele separately from SB and anencephaly. We also were able to exclude well-defined syndromic cases of encephalocele from our study, which allowed us to better explore the etiology of encephalocele; this exclusion may not be possible in other databases. Finally, our study was able to examine the impact of fortification of the grain supply on the prevalence of encephalocele, separate from SB and anencephaly, which has not been reported previously in the literature.
A limitation of this study is the rarity of encephalocele. The small number of cases of encephalocele limited our ability to conduct adjusted analyses and may have limited our ability to detect a significant difference in prevalence between black and white infants. Paucity of information on race and ethnicity for Hispanic, Asian, and Native American infants did not allow us to examine the variation in prevalence of encephalocele, SB, and anencephaly by Hispanic and Asian status as has been highlighted in recent literature. The use of only live births in the denominator limited our ability to calculate true rates, but the relatively small number of stillbirths among all births (<1%) is unlikely to bias the rate estimates appreciably. Limitations by ascertainment period included a potential for falsely lowered prevalence rates from 1981–1994, when prenatal diagnosis of birth defects became more common in Atlanta, but MACDP did not collect any information on infants and fetuses with birth defects delivered or electively terminated outside of the hospital setting. However, starting in 1994, MACDP began to include outpatient prenatal diagnostic settings as sources for information on infants and fetuses with birth defects. Finally, we used mandatory fortification of the grain supply in 1998 to assess the impact of folic acid on encephalocele, SB, and anencephaly. This proxy measure does not necessarily reflect the level of folic acid consumption at the individual level. Information regarding preconception folic acid supplementation, consumption of grains, and red blood cell folate levels, which are better indicators of individual folate status, were not available for this study.
Our findings show that encephalocele, SB, and anencephaly are similar in important characteristics, suggesting that encephalocele may be related to SB and anencephaly. However, we do not have sufficient evidence to recommend inclusion of encephalocele in NTD prevention evaluation efforts. Additional insight into possible etiologic heterogeneity between encephalocele and other NTDs may be better obtained by means of a case-control study using individual measures of folic acid intake and evaluation of a wider group of possible risk factors.
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ACKNOWLEDGMENTS |
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We thank all of the Metropolitan Atlanta Congenital Defect program collaborators who collected and reviewed the information, including Dr Richard Olney, and the Georgia Department of Human Resources for providing vital record data. We also thank Lilah Besser of the National Center on Birth Defects and Developmental Disabilities for her valuable technical support.
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FOOTNOTES |
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Accepted Mar 28, 2006.
Address correspondence to Adolfo Correa, MD, PhD, National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, 1600 Clifton Rd, Mailstop E-86, Atlanta, GA 30333. E-mail: acorrea{at}cdc.gov
The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the Centers for Disease Control and Prevention.
The authors have indicated they have no financial relationships relevant to this article to disclose.
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PEDIATRICS (ISSN 1098-4275). ©2006 by the American Academy of Pediatrics
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