Prenatal Exposure to Cigarettes, Alcohol, and Coffee and the Risk for Febrile Seizures
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《小儿科》
Perinatal Epidemiology Research Unit, Department of Obstetrics and Paediatrics, Aarhus University, Aarhus, Denmark
The Danish Epidemiology Science Center at the Institute of Public Health, University of Aarhus, Aarhus, Denmark
Department of Paediatrics, Aarhus University Hospital, Skejby, Denmark
Department of Obstetrics and Gynaecology, Hvidovre Hospital, Hvidovre, Denmark
ABSTRACT
Objective. Febrile seizure is a common type of seizure in childhood, probably caused by both genetic and early environmental factors. Little is known about the effect of environmental factors that operate in prenatal life, although the fetal brain may be particular vulnerable as a result of extensive brain growth and differentiation in this period. We evaluated the association between prenatal exposure to cigarettes, alcohol, and coffee and the risk for febrile seizures in 2 population-based birth cohorts.
Methods. The Aarhus Birth Cohort consisted of 25196 children of mothers who were scheduled to deliver at Aarhus University Hospital (1989–1996). The Aalborg-Odense cohort consisted of 10400 children of women who attended antenatal care in Odense or Aalborg (1984–1987). Both cohorts were linked with the Danish National Hospital Register and followed until December 1998 with a complete follow-up. We extracted from medical records additional information on febrile seizures in children in the Aarhus Birth Cohort who were born between 1989 and 1992.
Results. We found a slightly increased risk for febrile seizures in children who were exposed to 10 or more cigarettes per day in the Aarhus Birth Cohort, but the corresponding association was weak in the Aalborg-Odense cohort. We found no association between maternal alcohol and coffee consumption and the risk for febrile seizures. The results were similar for simple and complex febrile seizures.
Conclusions. Our data suggest that prenatal exposure to low to moderate levels of alcohol and coffee has no impact on the risk for febrile seizures, whereas a modest smoking effect cannot be ruled out.
Key Words: alcohol/drug use epidemiology febrile seizures lifestyle factors maternal smoking
Abbreviations: DNHR, Danish National Hospital Register ICD, International Classification of Diseases HR, hazard ratios CI, confidence interval
Febrile seizures are the most common type of seizure in childhood, affecting 2% to 5% of all children between 3 months and 5 years of age.1,2 The cause remains unknown, but genes as well as early environmental factors are believed to play a causal role.3,4 Although the majority of febrile seizures are benign, it is clinically important to understand the underlying mechanism. Febrile seizures are a frightening experience for most parents, and prolonged febrile seizures may promote the development of temporal lobe epilepsy. Most etiologic studies on febrile seizures have focused on genetic factors; for that reason, little is known about environmental risk factors. The developing brain may be particularly vulnerable to environmental factors during the prenatal and early postnatal period because extensive brain growth and differentiation take place in this period.5,6 Cigarette smoking and alcohol and coffee consumption are common and preventable environmental factors with a number of biological effects. Maternal smoking reduces fetal oxygenation7 and impairs fetal blood flow,8,9 and it has been associated with afebrile seizures,10 impaired brain development,11–14 and delayed early speech development.15 Alcohol in high doses may cause cranial malformations, stunted growth, delayed psychomotor maturation, and impaired intellectual development (ie, fetal alcohol syndrome).16 Low to moderate average alcohol intake may affect fetal brain development,17–19 especially if large volumes are consumed on single occasions and high peak blood concentrations are reached.20,21 Caffeine accumulates in the developing brain of the fetus,22 and animal studies suggest that the fetal brain is sensitive to caffeine.23,24 However, little is known about the long- term effects of maternal coffee intake on the development of the brain,25 but no association was found with infant mental and motor development in 1 data source.17,26
The few previous studies that evaluated the association between maternal lifestyle factors and febrile seizures had conflicting results. Some27–29 but not all studies30 found that children who were exposed to cigarette smoke in fetal life had an increased risk for febrile seizures, and maternal alcohol intake was associated with an increased risk in 1 study29 but not in another.28 We do not know of any study that evaluated the effect of coffee on the risk for febrile seizures. We aimed to evaluate the association between prenatal exposure to cigarette smoke, alcohol, and coffee and the risk for febrile seizures.
METHODS
This study is based on data from 2 population-based birth cohorts in Denmark. In both cohorts, information on maternal lifestyle factors were collected by self-administrated questionnaires that were completed during pregnancy. In Denmark, a standard drink contains 12 g or 15 mL of pure alcohol, the equivalent of 1 normal beer, 1 glass of wine, or 40 mL of spirits, and a standard cup of coffee contains 150 mL and 100 mg of caffeine. Information on febrile seizures was obtained by linking the cohorts with the Danish National Hospital Register (DNHR). The diagnosis was confirmed by review of medical records in a subgroup of the children.
Aarhus Birth Cohort
All pregnant women who attended routine antenatal care at the Department of Obstetrics and Gynaecology, Aarhus University Hospital, Denmark, from September 1989 to August 1996 were invited to participate in the Aarhus Birth Cohort.31 At 16 weeks of gestation, 2 self-administrated questionnaires were mailed to the women. The basic questionnaire, which was used to generate the medical record, provided information on smoking habits, maternal alcohol intake, maternal age, chronic diseases, and obstetric history; the research questionnaire provided information on intake of coffee, marital status, school education, and occupational status. Information on pregnancy outcome was obtained from birth registration forms that were filled out by the attending midwife immediately after delivery. Before data entry, all birth registration forms were checked manually and compared with the medical records by a research midwife. The study population was restricted to 26324 children of Danish-speaking women who completed the basic questionnaire, which corresponds to >95% of the women with singleton pregnancies in the study area. We excluded multiple births, children who died or emigrated before the age of 3 months, and children with invalid civil registry number, leaving 25196 children for the analysis.
Aalborg-Odense Cohort
All pregnant women who attended antenatal care in Odense or Aalborg, Denmark, from April 1984 to April 1987 were invited to participate in the Aalborg-Odense cohort.32 At 36 weeks of gestation, the midwives handed out a questionnaire to the women. The questionnaire included questions on maternal smoking habits; maternal alcohol intake; number of binge-drinking episodes, which was defined as intake of >8 standard drinks per occasion; coffee intake; maternal age; marital status; school education; and occupational status. Information on chronic diseases, obstetric history, and pregnancy outcome was collected from birth certificates and the women's medical records. The study population was restricted to 11850 pregnancies of women who completed the questionnaire, corresponding to 86% of the women with singleton pregnancies in the study areas.32 We excluded multiple births, children with malformations, children who died or emigrated before the age of 3 months, and children with invalid civil registry number from the study, leaving a total of 10400 children for analysis.
Identification of Children With Febrile Seizure
We linked information from the 2 cohorts with the DNHR by means of the civil registry number assigned to all Danish citizens at birth. The DNHR contains information on all discharges from Danish hospitals since 1977, and outpatients have been included in the register since 1995.33 Diagnostic information is classified in the DNHR, according to a Danish version of the International Classification of Diseases (ICD); ICD-8 was used from 1977 to 1993, and ICD-10 was used from 1994 to 1998. The register includes up to 20 diagnoses for each hospital discharge. We included children with febrile seizures when they were registered with ICD-8 code 780.21 or ICD-10 code R56.0; were between 3 and 60 months of age at the time of discharge; and had no recorded history of nonfebrile seizures, cerebral palsy, severe head traumas, intracranial tumors, meningitis, or encephalitis. Simple febrile seizures were defined as generalized-onset seizures that lasted <15 minutes, did not recur within 24 hours, and involved no postictal neurologic abnormalities. Complex febrile seizures were defined as seizures that were focal, prolonged (>15 minutes), recurrent within 24 hours, or associated with postictal neurologic abnormalities, including Todd paresis. In Denmark, general practitioners are encouraged to admit children with a first episode of febrile seizures.
We aimed to extract from medical records more detailed information on the 417 children who had febrile seizures in the Aarhus Birth Cohort and were born between 1989 and 1992. We retrieved and reviewed 413 medical records from 30 different hospitals. We could not confirm the febrile seizures diagnosis of 17 children, and the medical records of 5 children with febrile seizures contained no information on the duration of the febrile seizure. The remaining 391 children were categorized as having simple (n = 284) or complex (n = 107) febrile seizures. In children who had been admitted more than once with febrile seizures, the classification was based on the first episode.
Statistical Analyses
We used Cox proportional hazard models to assess hazard ratios (HRs) and 95% confidence intervals (CIs) for febrile seizures according to prenatal exposure to cigarette smoking, alcohol, and coffee. Diagnostic plots were used to assess the proportional hazards assumptions. The period of follow-up for febrile seizures began at the age of 3 months and ended the day of admission for the first febrile seizure, at death, at the day of emigration, on the child's fifth birthday, or on December 31, 1998, whichever came first. We stratified the data by several possible confounders, which in addition to the other maternal lifestyle factors included age, education, and parity of the mother; cohabitation of the parents; and gender, gestational age at birth, birth weight, and birth weight for gestational age of the child. All variables that changed the point estimate at least 10% were included in the final model.34 Finally, we also constructed a model that included all of the variables mentioned in Table 1. The correlation matrix of the regression coefficients was inspected to determine whether associations between the independent variables gave rise to multicollinearity problems.
RESULTS
We identified 924 (3.7%) children in the Aarhus Birth Cohort and 378 (3.6%) children in the Aalborg-Odense cohort who had been registered at least once during the study period with febrile seizures in the DNHR. In both cohorts, children with febrile seizures were more likely to be first born, male, and small for gestational age; have shorter pregnancy duration; and have lower birth weight than children who were not hospitalized with febrile seizures during the study period (Table 1).
In the Aalborg-Odense cohort, children who were exposed to binge-drinking episodes did not have an increased risk for febrile seizures compared with children who had not been exposed to binge-drinking episodes (Table 3). No such data were available in the Aarhus Birth Cohort.
We found little confounding by any single factors, and none of them qualified for the final model according to the change-in-estimate criteria (data not shown). We also made a Cox regression analysis on the basis of all of the covariates in Table 1, but the results remained essentially unchanged (Tables 2–4).
DISCUSSION
We evaluated the associations between prenatal exposure to cigarette smoke, alcohol, and coffee and the risk for febrile seizures in 2 population-based birth cohorts. Except for smoking, these factors were not associated with the risk for febrile seizures. Even the results related to smoking were not convincing.
Prenatal smoking has previously been associated with a 2-fold increased risk for febrile seizures in 2 case-control studies, and the risk increased with the number of cigarettes smoked per day.28,29 As discussed by Klebanoff,35 however, these findings may be hampered by selection bias, and they conflict with those of 2 cohort studies that showed no36 or weak27 associations, respectively. We found a slightly increased risk for febrile seizures for children who were exposed in utero to 10 or more cigarettes per day in the Aarhus Birth Cohort. However, no dose-response relation was found, and the finding was only weakly supported by data from the Aalborg-Odense cohort.
The effect of prenatal alcohol exposures on the risk for febrile seizures has been evaluated in 2 case-control studies; Berg et al28 found no associations, whereas Cassano et al29 found a 2-fold increased risk for complex febrile seizures and a strong dose-response relation. No association was found between alcohol and simple febrile seizures, and the authors suggested that simple and complex febrile seizures are etiologically distinct.29 We found no association between maternal alcohol intake and febrile seizures, whether they were simple or complex. In fact, we found a trend in the opposite direction in the Aarhus Cohort, but the trend was not statistically significant and may be attributable to chance. Previous studies have assessed the risk on the basis of average alcohol intake per week. Animal studies have indicated that ingesting a given dose of alcohol within a few hours (ie, binge drinking) causes greater neuronal and behavioral impairment than ingesting the same dose gradually over several days.20 Little is known about the effect of binge drinking on the developing brain, but in 1 study population, binge drinking was associated with impaired learning, attention, and memory abilities at 7 years of age.17 Our data revealed no association between the number of binge-drinking episodes during pregnancy and febrile seizures. We had no information on the timing of binge drinking events, and our findings do not rule out even strong effects of alcohol during short time windows of critical brain development.21 Although pregnant women commonly consume coffee and the developing brain may be sensitive to caffeine,25 few epidemiologic studies have evaluated the impact of coffee on the health and development of the child.25 Reassuring, we found no association between maternal coffee intake and febrile seizures.
Our study has strengths and limitations. The data were collected prospectively and independent of parental recall, and a thorough data collection enabled us to adjust for various potential confounding factors. Although self-administrated questionnaires provide fairly good estimates of the overall distribution of smoking and alcohol and coffee intake among pregnant women,37–39 the questionnaires may underestimate the actual intake. Because of the prospective data collection, any misclassification of the exposure and outcome is most likely nondifferential, causing bias toward the null hypothesis.
Our cohorts included at least 85% of the women with singleton pregnancies in the study areas, and their children were followed in nationwide registries with complete follow-up. Thus, it is unlikely that selection bias masked any true association. Information on febrile seizures was obtained from the DNHR, which is known to vary in quality and completeness. We previously validated the diagnosis of febrile seizures in the DNHR in a population-based cohort study of 6664 children who were born in Aarhus, Denmark, between 1990 and 1992 and followed up until March 2001.40 We collected information on febrile seizures in the cohort using a parental questionnaire. All potential febrile seizures were confirmed by diagnostic telephone interview or review of medical records. We found that 323 (4.9%) had had febrile seizures, and 231 of those were registered in the DNHR (completeness: 71.5%; 95% CI: 66.3–76.4). The completeness increased with increasing duration of the febrile seizures, but it did not depend on hospital, gender of the child, family history of febrile seizures, maternal age, maternal education, or maternal postnatal smoking habits. The diagnosis was confirmed in 231 of 249 children who were registered with febrile seizures in the DNHR (predictive value of a positive registration: 92.8%; 95% CI: 88.8–95.7). Thus, the registration of febrile seizures in the DNHR seems to be relatively complete and valid probably because febrile seizures are a frightening experience for most parents, the general practitioners are encouraged to admit children with a first episode of febrile seizures, Denmark is a small country and most inhabitants can reach a hospital within a short driving distance, and all treatments in Danish hospitals are tax financed and free of charge for the patients.
We conclude that prenatal exposure to a low to moderate intake of alcohol and coffee was not associated with the risk for febrile seizures in our data, whereas a small smoking effect could not be ruled out. Our findings do not rule out even strong effects of a high intake of cigarettes, alcohol, or coffee on a single occasion during short time windows of critical brain development.
ACKNOWLEDGMENTS
This study was supported by grants from the Danish Medical Research Council, Ronald McDonald House Charities, Danish Epilepsy Society, and the family foundation Hede Nielsen. The activities of the Danish Epidemiology Science Centre are financed by a grant from the National Danish Research Foundation.
FOOTNOTES
Accepted Feb 4, 2005.
No conflict of interest declared.
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Streissguth AP, Barr HM, Sampson PD. Moderate prenatal alcohol exposure: effects on child IQ and learning problems at age 7 1/2 years. Alcohol Clin Exp Res. 1990;14 :662 –669
Jacobson JL, Jacobson SW. Drinking moderately and pregnancy. Effects on child development. Alcohol Res Health. 1999;23 :25 –30
Bonthius DJ, West JR. Alcohol-induced neuronal loss in developing rats: increased brain damage with binge exposure. Alcohol Clin Exp Res. 1990;14 :107 –118
Kesmodel U. Binge drinking in pregnancy-frequency and methodology. Am J Epidemiol. 2001;154 :777 –782
Galli C, Spano PF, Szyszka K. Accumulation of caffeine and its metabolites in rat fetal brain and liver. Pharmacol Res Commun. 1975;7 :217 –221
Concannon JT, Braughler JM, Schechter MD. Pre- and postnatal effects of caffeine on brain biogenic amines, cyclic nucleotides and behavior in developing rats. J Pharmacol Exp Ther. 1983;226 :673 –679
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Vestergaard M, Obel C, Henriksen TB, et al. The Danish National Hospital Register is a valuable study base for epidemiological research in febrile seizures. J Clin Epidemiol. In press(Mogens Vestergaard, MD, P)
The Danish Epidemiology Science Center at the Institute of Public Health, University of Aarhus, Aarhus, Denmark
Department of Paediatrics, Aarhus University Hospital, Skejby, Denmark
Department of Obstetrics and Gynaecology, Hvidovre Hospital, Hvidovre, Denmark
ABSTRACT
Objective. Febrile seizure is a common type of seizure in childhood, probably caused by both genetic and early environmental factors. Little is known about the effect of environmental factors that operate in prenatal life, although the fetal brain may be particular vulnerable as a result of extensive brain growth and differentiation in this period. We evaluated the association between prenatal exposure to cigarettes, alcohol, and coffee and the risk for febrile seizures in 2 population-based birth cohorts.
Methods. The Aarhus Birth Cohort consisted of 25196 children of mothers who were scheduled to deliver at Aarhus University Hospital (1989–1996). The Aalborg-Odense cohort consisted of 10400 children of women who attended antenatal care in Odense or Aalborg (1984–1987). Both cohorts were linked with the Danish National Hospital Register and followed until December 1998 with a complete follow-up. We extracted from medical records additional information on febrile seizures in children in the Aarhus Birth Cohort who were born between 1989 and 1992.
Results. We found a slightly increased risk for febrile seizures in children who were exposed to 10 or more cigarettes per day in the Aarhus Birth Cohort, but the corresponding association was weak in the Aalborg-Odense cohort. We found no association between maternal alcohol and coffee consumption and the risk for febrile seizures. The results were similar for simple and complex febrile seizures.
Conclusions. Our data suggest that prenatal exposure to low to moderate levels of alcohol and coffee has no impact on the risk for febrile seizures, whereas a modest smoking effect cannot be ruled out.
Key Words: alcohol/drug use epidemiology febrile seizures lifestyle factors maternal smoking
Abbreviations: DNHR, Danish National Hospital Register ICD, International Classification of Diseases HR, hazard ratios CI, confidence interval
Febrile seizures are the most common type of seizure in childhood, affecting 2% to 5% of all children between 3 months and 5 years of age.1,2 The cause remains unknown, but genes as well as early environmental factors are believed to play a causal role.3,4 Although the majority of febrile seizures are benign, it is clinically important to understand the underlying mechanism. Febrile seizures are a frightening experience for most parents, and prolonged febrile seizures may promote the development of temporal lobe epilepsy. Most etiologic studies on febrile seizures have focused on genetic factors; for that reason, little is known about environmental risk factors. The developing brain may be particularly vulnerable to environmental factors during the prenatal and early postnatal period because extensive brain growth and differentiation take place in this period.5,6 Cigarette smoking and alcohol and coffee consumption are common and preventable environmental factors with a number of biological effects. Maternal smoking reduces fetal oxygenation7 and impairs fetal blood flow,8,9 and it has been associated with afebrile seizures,10 impaired brain development,11–14 and delayed early speech development.15 Alcohol in high doses may cause cranial malformations, stunted growth, delayed psychomotor maturation, and impaired intellectual development (ie, fetal alcohol syndrome).16 Low to moderate average alcohol intake may affect fetal brain development,17–19 especially if large volumes are consumed on single occasions and high peak blood concentrations are reached.20,21 Caffeine accumulates in the developing brain of the fetus,22 and animal studies suggest that the fetal brain is sensitive to caffeine.23,24 However, little is known about the long- term effects of maternal coffee intake on the development of the brain,25 but no association was found with infant mental and motor development in 1 data source.17,26
The few previous studies that evaluated the association between maternal lifestyle factors and febrile seizures had conflicting results. Some27–29 but not all studies30 found that children who were exposed to cigarette smoke in fetal life had an increased risk for febrile seizures, and maternal alcohol intake was associated with an increased risk in 1 study29 but not in another.28 We do not know of any study that evaluated the effect of coffee on the risk for febrile seizures. We aimed to evaluate the association between prenatal exposure to cigarette smoke, alcohol, and coffee and the risk for febrile seizures.
METHODS
This study is based on data from 2 population-based birth cohorts in Denmark. In both cohorts, information on maternal lifestyle factors were collected by self-administrated questionnaires that were completed during pregnancy. In Denmark, a standard drink contains 12 g or 15 mL of pure alcohol, the equivalent of 1 normal beer, 1 glass of wine, or 40 mL of spirits, and a standard cup of coffee contains 150 mL and 100 mg of caffeine. Information on febrile seizures was obtained by linking the cohorts with the Danish National Hospital Register (DNHR). The diagnosis was confirmed by review of medical records in a subgroup of the children.
Aarhus Birth Cohort
All pregnant women who attended routine antenatal care at the Department of Obstetrics and Gynaecology, Aarhus University Hospital, Denmark, from September 1989 to August 1996 were invited to participate in the Aarhus Birth Cohort.31 At 16 weeks of gestation, 2 self-administrated questionnaires were mailed to the women. The basic questionnaire, which was used to generate the medical record, provided information on smoking habits, maternal alcohol intake, maternal age, chronic diseases, and obstetric history; the research questionnaire provided information on intake of coffee, marital status, school education, and occupational status. Information on pregnancy outcome was obtained from birth registration forms that were filled out by the attending midwife immediately after delivery. Before data entry, all birth registration forms were checked manually and compared with the medical records by a research midwife. The study population was restricted to 26324 children of Danish-speaking women who completed the basic questionnaire, which corresponds to >95% of the women with singleton pregnancies in the study area. We excluded multiple births, children who died or emigrated before the age of 3 months, and children with invalid civil registry number, leaving 25196 children for the analysis.
Aalborg-Odense Cohort
All pregnant women who attended antenatal care in Odense or Aalborg, Denmark, from April 1984 to April 1987 were invited to participate in the Aalborg-Odense cohort.32 At 36 weeks of gestation, the midwives handed out a questionnaire to the women. The questionnaire included questions on maternal smoking habits; maternal alcohol intake; number of binge-drinking episodes, which was defined as intake of >8 standard drinks per occasion; coffee intake; maternal age; marital status; school education; and occupational status. Information on chronic diseases, obstetric history, and pregnancy outcome was collected from birth certificates and the women's medical records. The study population was restricted to 11850 pregnancies of women who completed the questionnaire, corresponding to 86% of the women with singleton pregnancies in the study areas.32 We excluded multiple births, children with malformations, children who died or emigrated before the age of 3 months, and children with invalid civil registry number from the study, leaving a total of 10400 children for analysis.
Identification of Children With Febrile Seizure
We linked information from the 2 cohorts with the DNHR by means of the civil registry number assigned to all Danish citizens at birth. The DNHR contains information on all discharges from Danish hospitals since 1977, and outpatients have been included in the register since 1995.33 Diagnostic information is classified in the DNHR, according to a Danish version of the International Classification of Diseases (ICD); ICD-8 was used from 1977 to 1993, and ICD-10 was used from 1994 to 1998. The register includes up to 20 diagnoses for each hospital discharge. We included children with febrile seizures when they were registered with ICD-8 code 780.21 or ICD-10 code R56.0; were between 3 and 60 months of age at the time of discharge; and had no recorded history of nonfebrile seizures, cerebral palsy, severe head traumas, intracranial tumors, meningitis, or encephalitis. Simple febrile seizures were defined as generalized-onset seizures that lasted <15 minutes, did not recur within 24 hours, and involved no postictal neurologic abnormalities. Complex febrile seizures were defined as seizures that were focal, prolonged (>15 minutes), recurrent within 24 hours, or associated with postictal neurologic abnormalities, including Todd paresis. In Denmark, general practitioners are encouraged to admit children with a first episode of febrile seizures.
We aimed to extract from medical records more detailed information on the 417 children who had febrile seizures in the Aarhus Birth Cohort and were born between 1989 and 1992. We retrieved and reviewed 413 medical records from 30 different hospitals. We could not confirm the febrile seizures diagnosis of 17 children, and the medical records of 5 children with febrile seizures contained no information on the duration of the febrile seizure. The remaining 391 children were categorized as having simple (n = 284) or complex (n = 107) febrile seizures. In children who had been admitted more than once with febrile seizures, the classification was based on the first episode.
Statistical Analyses
We used Cox proportional hazard models to assess hazard ratios (HRs) and 95% confidence intervals (CIs) for febrile seizures according to prenatal exposure to cigarette smoking, alcohol, and coffee. Diagnostic plots were used to assess the proportional hazards assumptions. The period of follow-up for febrile seizures began at the age of 3 months and ended the day of admission for the first febrile seizure, at death, at the day of emigration, on the child's fifth birthday, or on December 31, 1998, whichever came first. We stratified the data by several possible confounders, which in addition to the other maternal lifestyle factors included age, education, and parity of the mother; cohabitation of the parents; and gender, gestational age at birth, birth weight, and birth weight for gestational age of the child. All variables that changed the point estimate at least 10% were included in the final model.34 Finally, we also constructed a model that included all of the variables mentioned in Table 1. The correlation matrix of the regression coefficients was inspected to determine whether associations between the independent variables gave rise to multicollinearity problems.
RESULTS
We identified 924 (3.7%) children in the Aarhus Birth Cohort and 378 (3.6%) children in the Aalborg-Odense cohort who had been registered at least once during the study period with febrile seizures in the DNHR. In both cohorts, children with febrile seizures were more likely to be first born, male, and small for gestational age; have shorter pregnancy duration; and have lower birth weight than children who were not hospitalized with febrile seizures during the study period (Table 1).
In the Aalborg-Odense cohort, children who were exposed to binge-drinking episodes did not have an increased risk for febrile seizures compared with children who had not been exposed to binge-drinking episodes (Table 3). No such data were available in the Aarhus Birth Cohort.
We found little confounding by any single factors, and none of them qualified for the final model according to the change-in-estimate criteria (data not shown). We also made a Cox regression analysis on the basis of all of the covariates in Table 1, but the results remained essentially unchanged (Tables 2–4).
DISCUSSION
We evaluated the associations between prenatal exposure to cigarette smoke, alcohol, and coffee and the risk for febrile seizures in 2 population-based birth cohorts. Except for smoking, these factors were not associated with the risk for febrile seizures. Even the results related to smoking were not convincing.
Prenatal smoking has previously been associated with a 2-fold increased risk for febrile seizures in 2 case-control studies, and the risk increased with the number of cigarettes smoked per day.28,29 As discussed by Klebanoff,35 however, these findings may be hampered by selection bias, and they conflict with those of 2 cohort studies that showed no36 or weak27 associations, respectively. We found a slightly increased risk for febrile seizures for children who were exposed in utero to 10 or more cigarettes per day in the Aarhus Birth Cohort. However, no dose-response relation was found, and the finding was only weakly supported by data from the Aalborg-Odense cohort.
The effect of prenatal alcohol exposures on the risk for febrile seizures has been evaluated in 2 case-control studies; Berg et al28 found no associations, whereas Cassano et al29 found a 2-fold increased risk for complex febrile seizures and a strong dose-response relation. No association was found between alcohol and simple febrile seizures, and the authors suggested that simple and complex febrile seizures are etiologically distinct.29 We found no association between maternal alcohol intake and febrile seizures, whether they were simple or complex. In fact, we found a trend in the opposite direction in the Aarhus Cohort, but the trend was not statistically significant and may be attributable to chance. Previous studies have assessed the risk on the basis of average alcohol intake per week. Animal studies have indicated that ingesting a given dose of alcohol within a few hours (ie, binge drinking) causes greater neuronal and behavioral impairment than ingesting the same dose gradually over several days.20 Little is known about the effect of binge drinking on the developing brain, but in 1 study population, binge drinking was associated with impaired learning, attention, and memory abilities at 7 years of age.17 Our data revealed no association between the number of binge-drinking episodes during pregnancy and febrile seizures. We had no information on the timing of binge drinking events, and our findings do not rule out even strong effects of alcohol during short time windows of critical brain development.21 Although pregnant women commonly consume coffee and the developing brain may be sensitive to caffeine,25 few epidemiologic studies have evaluated the impact of coffee on the health and development of the child.25 Reassuring, we found no association between maternal coffee intake and febrile seizures.
Our study has strengths and limitations. The data were collected prospectively and independent of parental recall, and a thorough data collection enabled us to adjust for various potential confounding factors. Although self-administrated questionnaires provide fairly good estimates of the overall distribution of smoking and alcohol and coffee intake among pregnant women,37–39 the questionnaires may underestimate the actual intake. Because of the prospective data collection, any misclassification of the exposure and outcome is most likely nondifferential, causing bias toward the null hypothesis.
Our cohorts included at least 85% of the women with singleton pregnancies in the study areas, and their children were followed in nationwide registries with complete follow-up. Thus, it is unlikely that selection bias masked any true association. Information on febrile seizures was obtained from the DNHR, which is known to vary in quality and completeness. We previously validated the diagnosis of febrile seizures in the DNHR in a population-based cohort study of 6664 children who were born in Aarhus, Denmark, between 1990 and 1992 and followed up until March 2001.40 We collected information on febrile seizures in the cohort using a parental questionnaire. All potential febrile seizures were confirmed by diagnostic telephone interview or review of medical records. We found that 323 (4.9%) had had febrile seizures, and 231 of those were registered in the DNHR (completeness: 71.5%; 95% CI: 66.3–76.4). The completeness increased with increasing duration of the febrile seizures, but it did not depend on hospital, gender of the child, family history of febrile seizures, maternal age, maternal education, or maternal postnatal smoking habits. The diagnosis was confirmed in 231 of 249 children who were registered with febrile seizures in the DNHR (predictive value of a positive registration: 92.8%; 95% CI: 88.8–95.7). Thus, the registration of febrile seizures in the DNHR seems to be relatively complete and valid probably because febrile seizures are a frightening experience for most parents, the general practitioners are encouraged to admit children with a first episode of febrile seizures, Denmark is a small country and most inhabitants can reach a hospital within a short driving distance, and all treatments in Danish hospitals are tax financed and free of charge for the patients.
We conclude that prenatal exposure to a low to moderate intake of alcohol and coffee was not associated with the risk for febrile seizures in our data, whereas a small smoking effect could not be ruled out. Our findings do not rule out even strong effects of a high intake of cigarettes, alcohol, or coffee on a single occasion during short time windows of critical brain development.
ACKNOWLEDGMENTS
This study was supported by grants from the Danish Medical Research Council, Ronald McDonald House Charities, Danish Epilepsy Society, and the family foundation Hede Nielsen. The activities of the Danish Epidemiology Science Centre are financed by a grant from the National Danish Research Foundation.
FOOTNOTES
Accepted Feb 4, 2005.
No conflict of interest declared.
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