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American Journal of Epidemiology Advance Access originally published online on December 8, 2008
American Journal of Epidemiology 2009 169(3):313-322; doi:10.1093/aje/kwn334
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American Journal of Epidemiology © The Author 2008. Published by the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org.

ORIGINAL CONTRIBUTIONS

Binge Drinking During Pregnancy and Risk of Seizures in Childhood: A Study Based on the Danish National Birth Cohort

Yuelian Sun, Katrine Strandberg-Larsen, Mogens Vestergaard, Jakob Christensen, Anne-Marie Nybo Andersen, Morten Grønbæk and Jørn Olsen

Correspondence to Dr. Yuelian Sun, Department of Epidemiology, University of Aarhus, Vennelyst Boulevard 6, Building 1260, DK-8000 Aarhus C, Denmark (e-mail: ys{at}soci.au.dk).

Received for publication June 23, 2008. Accepted for publication September 18, 2008.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
Seizures are often found in children with fetal alcohol syndrome, but it is not known whether binge drinking during pregnancy by nonalcoholic women is associated with an increased risk of seizure disorders in children. The authors conducted a population-based cohort study of 80,526 liveborn singletons in the Danish National Birth Cohort (1996–2002). Information on maternal binge drinking (intake of ≥5 drinks on a single occasion) was collected in 2 computer-assisted telephone interviews during pregnancy. Children were followed for up to 8 years. Information on neonatal seizures, epilepsy, and febrile seizures was retrieved from the Danish National Hospital Register. Results showed that exposure to binge drinking episodes during pregnancy was not associated with an increased risk of seizure disorders in children, except for those exposed at 11–16 gestational weeks. These children had a 3.15-fold increased risk of neonatal seizures (95% confidence interval: 1.37, 7.25) and a 1.81-fold increased risk of epilepsy (95% confidence interval: 1.13, 2.90). These findings suggest that maternal binge drinking during a specific time period of pregnancy may be associated with an increased risk of specific seizure disorders in the offspring. The results are exploratory, however, and need to be replicated.

cohort studies; epilepsy; fetal alcohol syndrome; infant, newborn; prenatal exposure delayed effects; seizures, febrile

Abbreviations: ICD-10, International Statistical Classification of Diseases and Related Health Problems, Tenth Revision


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
Maternal consumption of large quantities of alcohol during pregnancy is a proven cause of fetal alcohol syndrome characterized by facial malformations, stunted growth, delayed psychomotor maturation, and impaired intellectual development (1, 2). Epilepsy is often found in children with fetal alcohol syndrome (3–6), and animal studies have shown that prenatal exposure to high levels of alcohol during the brain growth spurt increases susceptibility to seizures (7, 8), although these findings have not been consistent (9, 10).

A high intake of alcohol within a short period of time appears to be more neurotoxic than the same amount consumed over several days (11, 12). Animal studies have shown that even a single day of alcohol exposure during vulnerable time periods of prenatal brain growth affects brain development (12–15). A 2-fold higher risk of complex febrile seizures in children prenatally exposed to maternal alcohol consumption has been reported (16), but we have not been able to replicate this finding (17). Still, an effect of alcohol during vulnerable time periods of fetal brain development cannot be ruled out.

In this study, we examined whether binge drinking during specific gestational time periods is associated with an increased risk of neonatal seizures, epilepsy, and febrile seizures in a large population-based pregnancy cohort of nonalcoholic Danish women who binge drink occasionally (18, 19).


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 References
 
Study population
The present study is based on data from the population-based Danish National Birth Cohort of pregnant women and their offspring (20). At their first antenatal care visit between March 1996 and November 2002, pregnant women were invited to participate by their general practitioner. Information on exposures during pregnancy stems from 3 computer-assisted telephone interviews, which took place at approximately pregnancy week 17 (quartile: 14–20), pregnancy week 32 (quartile: 30–34), and 6 months after the delivery (quartile: 5–6). Details on study design and recruitment procedures of the Danish National Birth Cohort have been published elsewhere (20), and an English version of the interviews is available on the Web at www.ssi.dk/sw9653.asp. All regional ethics committees in Denmark approved establishment of the cohort, and the study was approved by the Danish Data Protection Agency.

We identified all 86,783 liveborn singletons whose mothers participated in the first interview. Children were excluded if their mothers did not provide complete information on binge drinking (n = 330), gave no information on gestational age at the time of the interview (n = 878), or had a discrepancy of more than 1 week between self-reported gestational age and gestational age as recorded in the Danish Medical Birth Registry (n = 4,441). Children whose mothers provided no information on weekly alcohol consumption during pregnancy (n = 75), smoking (n = 86), parity (n = 50), time to pregnancy and infertility treatment (n = 217), or household socio-occupational status (n = 180) were also excluded, leaving data on 80,526 children eligible for the analyses.

Alcohol consumption, including binge drinking, during pregnancy
Information on alcohol consumption during pregnancy was obtained from only the first 2 interviews, since information from the third interview was retrospectively collected in relation to the outcomes under study. In the first interview, the women reported their average weekly intake of beer, wine, and spirits and any binge drinking episodes while pregnant. We defined 1 drink as 1 bottle of beer, 1 glass of wine, or 1 glass of spirits (about 4 cL), each of which corresponds to about 12 g of alcohol in Denmark. Average alcohol consumption per week was calculated by adding the drinks of beer, wine, and spirits. Women who reported less than 1 drink per week were assigned a numeric value of 0.5 drink. Average alcohol consumption per week was categorized as nondrinker, 0.5–1.5 drinks, 2–3.5 drinks, and 4 or more drinks. Only 5% of nonabstainers reported drinking 4 or more drinks per week during pregnancy.

Binge drinking was defined as an intake of 5 or more drinks on a single occasion. Both the first and second interviews included information on the number and timing (gestational week) of binge drinking episodes from the beginning of pregnancy. We used information from only the first interview to quantify binge drinking from conception to the date of the first interview (18) and information from the second interview to cover the time period between the first and second interview. Timing of the binge episode in gestational weeks was dated from the first day of the last menstrual period. Number of binge drinking episodes was categorized into 4 groups (0, 1, 2, ≥3 episodes). To analyze binge drinking during specific gestational time periods, we used the following 5 time periods: a preconception period (pregnancy weeks 0–2), a fertilization and implantation period (pregnancy weeks 3–4), the embryonic period (pregnancy weeks 5–10), the early fetal period (pregnancy weeks 11–16), and the midfetal period (pregnancy weeks 17–30). This categorization was set before we began the analyses to make the gestational time periods as detailed as possible given the number of exposed children. Number of binge drinking episodes in each of these periods was categorized into 3 groups (0, 1, and ≥2 episodes); however, because data on exposure or outcome were sparse for the analysis of neonatal seizure and the analysis of febrile seizure and epilepsy in the late gestational periods, we used 2 groups of binge exposure for these analyses (0, ≥1 episodes).

Of the binge drinkers, 1,667 (8.0%) did not report the timing of at least one of their binge episodes (information on timing was lacking for 678 in the first interview, 885 in the second interview, and 104 in both interviews). The proportion of women for whom data on timing were missing increased with number of binge drinking episodes, indicating that missed reporting did not happen at random. We therefore imputed the timing of the undated binge episodes. Using the data that were complete regarding the timing of binge drinking, we set up a probability distribution of timing of binge drinking. For every undated binge episode, we defined a possible time period during which the episode could have occurred by using information on time of interview and timing of other reported binge episodes. The probability distribution of undated binge episodes was therefore conditioned on the possible time periods. The imputation procedure was repeated 5 times, resulting in 5 possible timing values for each undated binge episode (21).

Seizure disorders
Information on neonatal seizures, epilepsy, and febrile seizures was obtained from the Danish National Hospital Register (22), where diseases are coded according to the Danish version of the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10). Children were classified as having neonatal seizures if they had been hospitalized or had been in outpatient care after receiving a diagnosis of neonatal convulsion (ICD-10 code P90) during the neonatal period (the first 28 days of life), as having epilepsy (ICD-10 codes G40–G41) if they received a diagnosis after the neonatal period, and as having febrile seizures (ICD-10 code R56.0) if they received a diagnosis between 3 months and 5 years of age and had no history of epilepsy. Data on children with more than one diagnosis were included in each of the reported outcomes. The time of onset of neonatal seizures, febrile seizures, and epilepsy was set as the first day of admission or outpatient contact for the outcome of interest.

Potential confounders
Information on maternal age, gestational age at birth, Apgar scores at 5 minutes, and birth weight was obtained from the Danish Medical Birth Registry (23). Information on parity, household socio-occupational status, smoking status at the time of the first interview, and time to pregnancy was obtained from the first interview. Information on congenital malformations (ICD-10 codes Q00–Q99), cerebral palsy (ICD-10 code G80), and maternal history of epilepsy (International Classification of Diseases, Eighth Revision, code 345; ICD-10 code G40–G41) was obtained from the Danish National Hospital Register (22).

Statistical analysis
Time at risk started right after birth for neonatal seizure, at day 29 for epilepsy, and at day 90 for febrile seizure. Follow-up ended at onset of the outcomes of interest, death, end of follow-up (28th day for neonatal seizure, 5 years of age for febrile seizure), or end of the study period (December 31, 2005), whichever occurred first. We used Cox regression models with SAS version 9.1 software (SAS Institute, Inc., Cary, North Carolina) to estimate the incidence rate ratios of seizure disorders for children prenatally exposed to maternal alcohol consumption.

We estimated incidence rate ratios for neonatal seizures, epilepsy, and febrile seizures according to binge drinking and average alcohol consumption per week. We adjusted for gestational age at birth (<33, 33–36, 37–38, 39–41, ≥42 weeks), maternal age (15–24, 25–29, 30–34, 35–39, ≥40 years), parity (primiparous, multiparous), time to pregnancy (unplanned; 0–5, 6–12, ≥13 months without fertility treatment; infertility treatment), household socio-occupational status (higher-grade professionals, middle-grade professionals, skilled workers, unskilled workers, students, unemployed for >1 year), smoking status at the time of the first interview (no, stopped during pregnancy, 1–10, >10 cigarettes per day), and maternal history of epilepsy (yes, no). In the analysis of binge drinking related to risk of neonatal seizures, epilepsy, and febrile seizures, we also adjusted for average alcohol consumption. We further stratified the analyses according to sex and gestational age (preterm, term, postterm). We also conducted separate analyses for children with and without one or more of the following adverse outcomes: congenital malformations, cerebral palsy, Apgar score less than 7 or missing, preterm delivery, and missing or low (<2,500 g) birth weight. We stratified the analyses according to age at onset of febrile seizure (<1, 1, ≥2 years) and epilepsy (<1, 1–2, ≥3 years). Women with an unplanned pregnancy were more likely to binge drink in the early period of pregnancy, probably because they were less aware of the pregnancy than those whose pregnancy was planned. Furthermore, women with a planned pregnancy may provide a more concise timing of binge drinking. We therefore conducted part of the analyses restricted to those whose pregnancy was planned.

Then, we estimated the joint effect of binge drinking (0, 1, ≥2 episodes) and average alcohol consumption (0, <3, ≥3 drinks per week) by considering a reference of children born to women who did not binge drink and consume alcohol.

Finally, we estimated the incidence rate ratio for neonatal seizures, febrile seizures, and epilepsy among children prenatally exposed to binge drinking during different time periods of the pregnancy. We adjusted for the same set of potential confounders as mentioned above and average alcohol consumption furthermore to determine whether the effect measures changed. In this paper, we present the average incidence rate ratio estimates from the 5 imputations (21). We also restricted the analyses to women for whom information on timing was complete to determine whether our results were sensitive to the imputation method, that is, if the results from imputation were different from those based on originally available data on timing.

Some mothers who experienced more than one pregnancy participated in the cohort. Therefore, we examined whether the results changed by limiting the analyses to the first enrolled pregnancies (4,940 children were excluded from the study population of 80,526 singletons) or by using the robust sandwich estimate for the covariance matrix to adjust for clustering.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 References
 
Because of different follow-up periods, 80,526 children were included in the analysis for neonatal seizure, 80,358 for epilepsy, and 80,325 for febrile seizure. During follow-up, 134 children were diagnosed with neonatal seizure, 576 with epilepsy, and 3,089 with febrile seizure. Of the children with neonatal seizure, 23 (17%) were diagnosed with epilepsy later in life.

In the cohort, 36,075 (44.8%) mothers consumed at least half a drink of alcohol per week and 20,955 (26.0%) women reported at least one episode of binge drinking during pregnancy. Compared with mothers who reported no alcohol consumption, mothers who consumed at least half a drink per week were more often multiparous, older than 30 years of age, and of a higher socioeconomic status, and they were less likely to have a history of epilepsy. Mothers who binged were more often nulliparous, a smoker or previous smoker, and a student, and they became pregnant more often unintentionally and were on average of a higher socioeconomic status than mothers who did not consume alcohol during pregnancy (Table 1).


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  		Table 1. Characteristics of the Study Population of Women Stratified by Binge Drinking and Alcohol Consumption During Pregnancy, Denmark, 1996–2002

 
Neither alcohol consumption during pregnancy nor binge drinking was associated with an increased risk of neonatal seizures, febrile seizures, or epilepsy, and some incidence rate ratios were even less than 1 (Table 2). We found no interaction between binge drinking and average alcohol consumption during pregnancy on the risk of the seizure disorders of interest (Table 3). The associations were not modified by children's sex, gestational age, or adverse outcomes (congenital malformations, cerebral palsy, Apgar score <7, preterm delivery, and birth weight <2,500 g) and the time of onset of epilepsy and febrile seizure (data not shown).


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  		Table 2. Incidence Rate Ratios for Seizure Disorders Among Children Prenatally Exposed to Alcohol, Denmark, 1996–2002

 

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  		Table 3. Adjusted Incidence Rate Ratios for Seizure Disorders According to Average Alcohol Consumption (Drinks/Week) and Binge Drinking During Pregnancy, Denmark, 1996–2002

 
When we took timing of binge drinking episodes into account, children exposed to maternal binge drinking at 11–16 gestational weeks had a 3.15-fold increased risk of neonatal seizures (95% confidence interval: 1.37, 7.25) and a 1.81-fold increased risk of epilepsy (95% confidence interval: 1.13, 2.90) (Table 4). This association remained after adjustment for average alcohol consumption and when we restricted the analyses to women for whom information on timing of binge drinking was complete.


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  		Table 4. Incidence Rate Ratios for Seizure Disorders Among Children Prenatally Exposed to Binge Drinkinga at Specific Time Periods During Pregnancy, Denmark, 1996–2002

 
The estimated incidence rate ratios for neonatal seizures, epilepsy, and febrile seizures related to alcohol consumption during overall pregnancy and during specific gestational periods did not change much when we restricted the analysis to a subcohort of first-enrolled pregnancies. Adjustment for clustering did not change the precision of our estimates. Neither did the results change when we restricted the analyses to planned pregnancies, but the confidence intervals of the incidence rate ratio for neonatal seizure and epilepsy became wider and included 1 for binge drinking in gestational weeks 11–16.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
References
 
Our study showed that binge drinking during pregnancy in general was not associated with an increased risk of seizure disorders in offspring. When timing of binge drinking was taken into consideration, we found that exposure to binge drinking only during weeks 11–16 of gestation was associated with an increased risk of neonatal seizure and epilepsy in offspring. Although the aim of the study was to examine the association between time-specific exposures to binge drinking and risk of seizure disorders, our findings should be interpreted with caution and need to be replicated. We examined the associations of binge drinking with 3 outcomes in terms of both overall comparisons and comparisons for 5 different gestational periods. The majority of relative risk estimates for seizure disorders showed no or even negative associations. However, an increased risk of neonatal seizures and epilepsy was found for binge drinking in the same time period, which may indicate that weeks 11–16 are a particularly vulnerable time period in pregnancy, but the correlation between the 2 disorders should be considered.

Animal-model studies have shown that the type and severity of fetal alcohol effects on the central nervous system depend on both the pattern and timing of drinking episodes (11, 12, 24, 25). Even a single binge exposure may cause brain lesion when it occurs within the period of enhanced vulnerability (24). In gestational weeks 11–16 of human development, active neuron proliferation and migration occur, and this period is especially important for hippocampal and neocortical development of the brain (26–28). Alcohol exposure can affect the generation, proliferation, and migration of neurons (29–31), and many childhood epilepsies have been associated with a variety of neurodevelopmental defects in prenatal life (28). The time after 16 gestational weeks is also of interest, but the level of alcohol consumption in our study was too low to conduct meaningful analyses. A study of rats has shown that exposure to alcohol shortly after birth, which corresponds to the late pregnancy period in humans (32), promotes hippocampal seizures (33).

Our study has several strengths. Denmark is one of few countries with a long tradition of alcohol consumption during pregnancy, also among well-educated and socially advantaged women. Studying alcohol exposure in this population is less subject to confounding by poor diet or disadvantageous social factors than are studies of alcoholics (34). Some women who deliberately abstain from alcohol may do so for health reasons, but these health problems are likely not related to the outcomes we studied. Furthermore, we included children born to mothers who did not binge drink during pregnancy, who may exhibit non-binge-drinking behavior, as a reference when we explored the risk of seizure disorders for children prenatally exposed to maternal binge drinking. We did adjust for various potential confounding factors, including maternal history of epilepsy, smoking, and social status, but found only little change in the estimate of interest.

Early loss of embryos or fetuses after exposure to maternal alcohol consumption may reduce the association related to postnatal outcomes if these outcomes would have been more frequent in fetuses that did not survive because of the exposure. Both male and female alcohol intake during the week of conception may increase the risk of very early pregnancy loss (35), but, in the Danish National Birth Cohort, binge drinking is not associated with an increased risk of spontaneous abortion (36). However, binge drinking was associated with an increased risk of stillbirth (36).

Compared with self-administered questionnaires, interviews may provide an overall higher response rate for the specific questions on binge drinking (37). Furthermore, recall of alcohol consumption was reported before the seizure disorders occurred, and misclassification (most likely in the form of underreporting) is probably nondifferential with respect to the occurrence of seizures. This type of misclassification often induces bias toward the null hypothesis.

We obtained information on both inpatients and outpatients regarding neonatal seizures, epilepsy, and febrile seizures from the Danish National Hospital Register. Thus, we followed this large, population-based cohort with virtually no loss to follow-up, making selective loss of cases unlikely. The quality of the register data has been evaluated, with a positive predictive value of 81% (95% confidence interval: 75%, 87%) for epilepsy (38) and 93% (95% confidence interval: 89%, 96%) for febrile seizure (39). Completeness of registration on febrile seizures was found to be 72% (95% confidence interval: 66%, 76%) in the register system (39). We did not have complete data on neonatal seizures and epilepsy, but less severe cases of epilepsy may not be registered. We found that the incidence rate of epilepsy per 100,000 person-years in the first year of life for singletons in the Danish National Birth Cohort was slightly higher, 269.4 (95% confidence interval: 235.7, 307.9) versus 202.0, than for children born in Denmark during the same period (40). Oversampling of women with health problems such as infertility may be a possible reason (41).

Approximately 60% of invited women participated in the Danish National Birth Cohort, representing about 30% of the eligible pregnant women in Denmark during the study period. Most of the nonparticipating women were never invited because only 50% of general practitioners took part in the study (41). Compared with the background population, participants in the Danish National Birth Cohort were more often aged 25–34 years, nulliparous, and nonsmokers and had a normal body mass index (18.5–24.9 kg/m2) (41).

Epilepsy is not a single disease entity but comprises a variety of disorders reflecting underlying brain dysfunction that have many different causes. We had limited clinical data on subtypes of epilepsy and could not examine whether the association was restricted to specific types of epilepsy. Should that be the case, the association may be stronger.

In conclusion, our study indicates that maternal binge drinking during pregnancy weeks 11–16 may have a time-specific effect on the risk of some seizure disorders in the offspring. Such an effect of binge drinking will not be detectable if timing of exposure is not taken into consideration, even in large studies. The results are exploratory, however, and need to be replicated.


   ACKNOWLEDGMENTS
 
Author affiliations: Department of Epidemiology, Institute of Public Health, University of Aarhus, Aarhus, Denmark (Yuelian Sun, Jørn Olsen); Shanghai Institute of Planned Parenthood Research, Shanghai, China (Yuelian Sun); Center for Alcohol Research, National Institute of Public Health, University of Southern Denmark, Copenhagen, Denmark (Katrine Strandberg-Larsen, Morten Grønbæk); Department of General Practice, Institute of Public Health, University of Aarhus, Aarhus, Denmark (Mogens Vestergaard); Department of Neurology, Aarhus University Hospital, Aarhus, Denmark (Jakob Christensen); Department of Clinical Pharmacology, Aarhus University Hospital, Aarhus, Denmark (Jakob Christensen); Division of Epidemiology, Department of Public Health, University of Southern Denmark, Odense, Denmark (Anne-Marie Nybo Andersen); and Department of Epidemiology, School of Public Health, University of California at Los Angeles, Los Angeles, California (Jørn Olsen).

The study was supported by the Danish National Research Foundation, which established the Danish Epidemiology Science Centre that initiated and created the Danish National Birth Cohort. The cohort is a result of a major grant from this Foundation. Additional support for the Danish National Birth Cohort is obtained from the Pharmacy Foundation, the Egmont Foundation, the March of Dimes Birth Defects Foundation, the Augustinus Foundation, and the Health Foundation. None of the sponsors participated in the design and conduct of the study; in the collection, analysis, and interpretation of the data; or in the preparation, review, or approval of the manuscript.

Conflict of interest: none declared.


   References
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 

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