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ARTICLE |
a Departments of aEpidemiology
c General Practice, Institute of Public Health, University of Aarhus, Aarhus, Denmark
b Shanghai Institute of Planned Parenthood Research, Shanghai, China
d Department of Neurology and Department of Clinical Pharmacology, Aarhus University Hospital, Aarhus, Denmark
e Pediatric Infectious Diseases, Epidemiology and Immunology, Emory University, Atlanta, Georgia
f Department of Epidemiology, School of Public Health, University of California at Los Angeles, Los Angeles, California
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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METHODS. We included 90619 singletons who were born between September 1997 and June 2003 in the Danish National Birth Cohort and followed them up to December 2005. Information on maternal infections during pregnancy (cystitis, pyelonephritis, diarrhea, coughs lasting >1 week, vaginal yeast infection, genital herpes, venereal warts, and herpes labialis) was prospectively reported by mothers in 2 computer-assisted telephone interviews in early and midgestation; information on maternal cystitis and pyelonephritis during late period of pregnancy was also collected in a third interview after birth. Children who received a diagnosis of epilepsy as inpatients or outpatients were retrieved from the Danish National Hospital Register. We identified 646 children with a diagnosis of epilepsy during up to 8 years of follow-up time. Cox proportional hazards regression models were used to estimate incidence rate ratio and 95% confidence interval.
RESULTS. Children who were exposed to maternal cystitis, pyelonephritis, diarrhea, coughs, and/or vaginal yeast infection some maternal infections in prenatal life had an increased risk for epilepsy. Coughs lasting >1 week were associated with an increased risk for epilepsy only in the first year of life, as was vaginal yeast infection only in children who were born preterm. These associations remained unchanged for children without cerebral palsy, congenital malformation, or a low Apgar score at 5 minutes.
CONCLUSIONS. Prenatal exposure to some maternal infections was associated with an increased risk for epilepsy in childhood.
Key Words: epilepsy • infection • prenatal • pregnancy • cohort studies • etiology
Abbreviations: DNBC—Danish National Birth Cohort • ICD-10—International Classification of Diseases, 10th Revision • IRR—incidence rate ratio • CI—confidence interval
Epilepsy is a condition characterized by recurrent epileptic seizures,1 and it affects 1% of the population before the age of 202,3; however, <20% of these cases have a known cause.4 Maternal infections during pregnancy have been associated with an increased risk for cerebral palsy,5 mental retardation,6 and schizophrenia.7,8 Whether maternal infections play a role in the risk for epilepsy is unclear. The seasonal pattern of births of children with epilepsy indicates that infections or other environmental exposures with seasonal variation may play a causal role in the cause of epilepsy.9 A cohort study in Canada showed that maternal infections during pregnancy were associated with an increased incidence for epilepsy in childhood.10 This finding was in keeping with some11 but not all previous studies.12–15
Because short-term infections are difficult to recall accurately, studies on infections have to be based on prospectively collected data. We explored the association between specific infections during pregnancy and the risk for epilepsy in childhood using data from a large population-based birth cohort in Denmark with up to 8 years of almost complete follow-up.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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100000 pregnancies and their offspring.16 It was established to provide a data source for epidemiologic studies of short-term and long-term consequences of intrauterine exposures. Enrollment in the cohort took place between March 1996 and November 2002. General practitioners introduced the study to women at their first contact to the antenatal care system, and pregnant women were included when the signed consent form was received. Exposure during pregnancy was collected by 3 computer-assisted telephone interviews, which took place at approximately pregnancy weeks 17 (quartile: 14–20) and 32 (quartile: 30–34) and at 6 months (quartile: 5–6) after the delivery. Part of the third interview was designed to collect information during pregnancy after 30 gestational weeks. Details on the DNBC regarding study design and recruitment procedures have been published elsewhere,16 and the questionnaires are available at www.bsmb.dk. We identified all singletons who were born between September 1997 and June 2003 and whose mothers took part in 1 of the 3 interviews (N = 90819). Among them, 200 children died in the neonatal period, leaving 90619 for the analyses. The study was approved by the Danish Data Protection Agency, and the cohort itself was approved by all ethic research committees in Denmark.
Maternal Infections During Pregnancy
Information on cystitis, pyelonephritis, diarrhea, cough, vaginal yeast infection, genital herpes, venereal warts, and herpes labialis was collected from mothers according to highly structured questions. Information on cystitis and pyelonephritis was collected in the first, second, and third interviews; data on diarrhea, and vaginal yeast infection was collected in the first and second interviews; and data on coughs, genital herpes, venereal warts, and herpes labialis were collected in the second interview (Table 1). Diarrhea in the questionnaire was defined as 
3 defecations within 24 hours. Coughs were recorded when they lasted >1 week. Timing in gestation week for cystitis, pyelonephritis, diarrhea, cough, vaginal yeast infection and duration in day for diarrhea were collected. Information on maternal fever episodes during pregnancy was reported in the first 2 interviews independent of questions on infection.
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2 unprovoked seizure episodes.1
Potential Confounders
Information on parental age, gestational age at birth, method of delivery, and Apgar scores at 5 minutes were obtained from the Danish Medical Birth Registry.18 Information on maternal weight and height before pregnancy (BMI = weight [kg]/height [m]2), social status, and history of spontaneous abortion were obtained from the first interview of DNBC. Information on smoking was obtained in the first 2 interviews. Coding of social status was based on self-reported education and job titles at the time of recruitment. Women who had a higher education (4 years beyond secondary school education) or were in management were classified as "high" social status. Women with middle-range training and skilled workers were classified as "middle" social status, and unskilled workers and unemployed were classified as "low" social status. Information on parity was obtained from the Danish Medical Birth Registry, but, when unavailable, we used the information from the interview of DNBC (n = 2449). Data on congenital malformations (ICD-10 codes Q00–Q99), cerebral palsy (ICD-10 code G80), and maternal history of epilepsy (ICD-8 code 345; ICD-10 codes G40–G41), preeclampsia (ICD-10 codes O14–O15), diabetes during pregnancy (ICD-10 code O24), and premature rupture of membrane (ICD-10 code O42) were obtained from the Danish National Hospital Register.17 Small for gestational age was defined as a birth weight below the 10th percentile for gender-specific and gestational age-specific distributions of birth weight.
Statistical Analysis
The children were followed from day 29 after birth until the onset of epilepsy; death; or December 31, 2005, whichever came first. The incidence rate ratios (IRRs) of epilepsy and 95% confidence interval (CI) were estimated by using Cox proportional hazards regression models in Stata 9.2 (Stata Corp, College Station, TX). The IRR is defined as the ratio of the incidence rate for exposed children divided by the incidence rate for the nonexposed children. Given the almost complete follow-up and the low incidence of epilepsy, the IRRs are quite similar to relative risks. When the IRR varied over time, we reported the results for different time periods separately. We also estimated the association between maternal infections and the risk for epilepsy in the first 3 years of life. Women who reported both cystitis and pyelonephritis (n = 268) were grouped into the latter. We categorized diarrhea according to the duration of the episode (1, 2, 3, or 4 days). When >1 episode of diarrhea was reported, the longest was used.
We estimated IRRs of epilepsy after stratifying for calendar year of birth and adjusting for maternal age, paternal age, gestational age, parity, maternal social status, prepregnancy BMI, smoking, methods of delivery, history of spontaneous abortion, and maternal history of epilepsy. Besides maternal age, paternal age, and parity, we also selected other potential confounders, such as maternal social status, prepregnancy BMI, history of spontaneous abortion, maternal history of epilepsy, and smoking. These factors correlated with maternal infections and could affect the fetus. Method of delivery was adjusted for because infections during pregnancy may result in an increased risk for nonspontaneous deliveries. Robust standard errors (SEs) were used to adjust for dependence between different pregnancies (N = 12402; 13.7%) of woman who participated in the cohort twice or more. Information on cystitis and pyelonephritis during the late period of pregnancy was also collected from the third interview after birth, which may lead to differential recall bias; therefore, we restricted the analyses concerning cystitis and pyelonephritis to data from the first 2 interviews.
We did sensitivity analyses for missing values on infections. First, we included women who did not provide information on infections in the noninfected group for vaginal yeast infection (n = 1411), cystitis (n = 72), pyelonephritis (n = 55), diarrhea (n = 118), coughs (n = 859), herpes labialis (n = 1063), genital herpes (n = 854), and venereal warts (n = 929). The results shown were based on this strategy. Second, we included women with missing data into the infected group to evaluate whether it changed the estimates of association. Participants with a missing value on potential confounders, including parity (n = 119), smoking status (n = 391), or methods of delivery (n = 819), were excluded from the adjusted analysis. Participants with missing values on paternal age (n = 1226), BMI (n = 4906), maternal social status (n = 3836), and history of spontaneous abortion (n = 3507) were given a separate code and included in the analyses because most of the missing value (n = 3507) on BMI, social status, and history of spontaneous abortion were attributable to nonparticipation in the first interview. After the exclusions, 89290 children were included in the adjusted analyses involving the first 2 interviews and 84230 children in the adjusted analyses involving the second interview.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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The proportion of prenatal exposure to maternal infections among children with or without epilepsy is given in Table 1. The characteristics of the cohort according to the status of maternal infections are shown in Table 2. Because of limited space, we provided the characteristics of the cohort only according to cystitis, pyelonephritis, diarrhea, vaginal yeast infection, and coughs. Pregnant women with or without infections had different characteristics; for example, women with urinary tract infection more often were nulliparous, younger, and more overweight; had a low social class; smoked more; more often had preeclampsia or diabetes during pregnancy; and more often gave birth by cesarean section or assisted delivery (Table 2).
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4 days (IRR: 1.59; 95% CI: 1.15–2.19). Prenatal exposure to maternal coughs was associated with an increased risk for epilepsy in the first year of life (IRR: 1.55; 95% CI: 1.11–2.17); thereafter, the rate of epilepsy was similar to the rate for the nonexposed. Gestational age at birth modified the effect of vaginal yeast infection (P = .002) only. Prenatal exposure to maternal vaginal yeast infection was associated with an increased risk for epilepsy (IRR: 2.56; 95% CI: 1.43–4.61) among children who were born preterm but not among children who were born at term (IRR: 0.97; 95% CI: 0.78–1.20). We found no association between the risk for epilepsy and genital herpes, venereal warts, and herpes labialis.
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4 days, 1.23 (95% CI: 0.96–1.58) for coughs lasting > 1 week, and 2.79 (95% CI: 1.11–6.98) for vaginal yeast infection among children who were born preterm.
Most mothers with infections did not report fever episodes during pregnancy, including 8140 (69.6%) of the women with cystitis, 234 (51.3%) with pyelonephritis, 12779 (62.8%) with diarrhea, 7689 (57.0%) with coughs, 12951 (70.0%) with vaginal yeast infection, 965 (72.0%) with genital herpes, 540 (70.3%) with venereal warts, and 7488 (71.4%) with herpes labialis. Children who were prenatally exposed to maternal infections but without fever episodes during pregnancy still had an increased risk for epilepsy when exposed to maternal cystitis or pyelonephritis (IRR: 1.35; 95% CI: 1.06–1.73), maternal diarrheas (IRR: 1.26; 95% CI: 1.02–1.57), especially diarrhea lasting 4 days (IRR: 1.75; 95% CI: 1.18–2.59), coughs lasting >1 week among children in the first year of life (IRR: 1.66; 95% CI: 1.09–2.54), and maternal vaginal yeast infection among children born preterm (IRR: 2.36; 95% CI: 1.07–5.20).
Among 90619 children, 6551 (7.2%) had a diagnosis of congenital malformations, 209 (0.2%) children had cerebral palsy, and 1592 (1.8%) had an Apgar score at 5 minutes of <7 (536; 0.6%) or a missing value (1056; 1.2%). When we excluded children with congenital malformation, cerebral palsy, and low (<7) or missing Apgar score at 5 minutes, the IRR of epilepsy was 1.55 (95% CI: 1.23–1.96) for cystitis, 2.38 (95% CI: 1.06–5.35) for pyelonephritis, 1.50 (95% CI: 1.03–2.21) for diarrhea lasting 4 days, and 1.36 (95% CI: 0.89–2.08) for coughs lasting >1 week among children in the first year of life and 2.19 (95% CI: 1.03–4.70) for vaginal yeast infection among children who were born preterm. The associations between infections and the risk for epilepsy were similar among boys and girls (data not shown).
Maternal cystitis during each trimester and consistent diarrhea lasting 4 days in the first 2 trimesters were associated with an increased risk for epilepsy. Maternal coughs lasting >1 week during each trimester and maternal vaginal yeast infection in the first 2 trimesters were associated with an increased risk for epilepsy among children in the first year of life and among children who were born preterm, respectively, although part of these results were not statistically significant (Table 4). The sensitivity analyses showed that considering participants with missing values on infection as being infected did not change the results substantially from those shown here except for genital herpes (IRR: 1.53, 95% CI: 1.53, 1.01–2.32).
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Our study was based on prospectively collected data on infections. Most information on maternal infections was collected in 2 interviews while the mothers were in the early and middle periods of pregnancy. Our study is 1 of the few studies that examined the association between maternal infections in the first 2 trimesters, rather than from the time period of admission for delivery. Information on cystitis and pyelonephritis during the late period of pregnancy was collected from the third interview after birth, which may cause differential recall bias, but results from whole data were similar to what we found in data obtained before delivery.
Almost all pregnant women in Denmark attend the antenatal care program, which includes 3 visits to the general practitioner and 7 visits to the midwife. In this antenatal care program, urine samples are screened for infection, protein, and glucose. The routine is that the urine sample is screened by dipstick or microscopy first and then cultured if the screening results are positive. The reported cystitis by participants may, therefore, include asymptomatic bacteriuria, which affects 5% to 10% of pregnant women.19 Unfortunately, we were not able to stratify episodes of cystitis by symptoms. The prevalence of urinary tract infection in our study (13.7%) was similar to the report (15.6%) from the study based on the National Collaborative Perinatal Project20 but lower than that (20.9%) from another population-based study.6 Information on other infections in our study may have been based on symptoms or clinical examinations. The proportion of women who reported vaginal yeast infection (20.4%) in our study was similar to what has been found in another study (21.1%) on the basis of clinical inspections.21
We have been able to consider several potential confounders. We adjusted for gestational age, maternal age, smoking, methods of delivery, history of spontaneous abortion, and maternal history of epilepsy but found limited confounding. Maternal infections were also associated with an increased risk for pregnancy complications, such as preeclampsia and diabetes. We cannot exclude that having an infection is a marker of a higher risk for epilepsy of other reasons (confounding); neither can we exclude that infections cause unrecorded pregnancy complications that lead to epilepsy.
Data on epilepsy were obtained from the Danish Hospital Registry, which holds information on all children who are treated for epilepsy at somatic hospitals as inpatients or outpatients. Epilepsy in childhood is considered a serious disease that requires treatment by specialists, and treatment in Danish hospitals is free. Some types of epilepsy, such as childhood absence epilepsy, may not be severe enough to warrant visits to hospitals. An incomplete registration of epilepsy will introduce bias only when it depends on maternal infections during pregnancy, which we found unlikely because information on maternal infections was prospectively collected before the diagnoses of epilepsy. The positive predictive value of the epilepsy diagnosis in the registry has been estimated to be 81% (95% CI: 75%–87%).22 The true validity of the epilepsy diagnosis is even higher because 40% of those who did not fulfill the criteria for epilepsy (at least 2 unprovoked seizures on separate days) had experienced a single unprovoked seizure, which may signify yet-undiagnosed epilepsy. Our study was limited by a lack of specific clinical information on epilepsy, and we cannot examine whether the association was restricted to specific types of epilepsy.
Approximately 30% of all Danish pregnant women in the recruitment period were included in the cohort, but approximately half of those who did not participate were never invited because their general practitioners did not take part in the study. It has previously been shown that the internal validity of a study need not be biased by a low participation in the cohort.23
Increasing evidence suggests that infections during pregnancy are associated with abnormal fetal brain development and neuromental disorders later in life.5–8 Although the mechanisms underlying the associations remain unsettled, it is possible that cytokines produced by the immune system during the course of maternal infection may harm the developing brain.24,25 A high concentration of certain cytokines in amniotic fluid and neonatal blood has for example been associated with cerebral palsy.26,27
Molecular mimicry with cross-reaction between antibodies to epitopes of infectious agents and the common epitopes of the nervous system may provide another causal pathway.8 Campylobacter jejuni is a common bacterial diarrheal agent that contains several gangliosides similar to those found at different stages in the fetal brain.8,28 Escherichia coli is the primary pathogen of maternal urinary tract infections29; E coli K1 contains polysialic acid in its capsule, similar to the polysialic acid found with the neural cell adhesion molecule, which plays an important role in the development of the brain.30 Interestingly, early reports suggest that gangliosides changes with epilepsy in the hippocampus and anti-gangliosides (GM1) antibodies may be related to certain types of epilepsy in human beings.31,32
Fever may play a role in the association between maternal infections and the risk for epilepsy. Animal experiments show that hyperthermia is a potential teratogen in many species,33 but our data showed associations even for infections without fever. Some of the associations are likely caused by chance because of the number of comparisons that we made.
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CONCLUSIONS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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Address correspondence to Yuelian Sun, MD, Department of Epidemiology, University of Aarhus, Vennelyst Boulevard 6, Aarhus, 8000 C, Denmark. E-mail: ys{at}soci.au.dk
The authors have indicated they have no financial relationships relevant to this article to disclose.
| What's Known on This Subject Maternal infections have been associated with an increased risk of some neurological disorders. Whether maternal infections play a role for the risk of epilepsy is unclear.
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| What This Study Adds Prenatal exposure to several maternal infections, including cystitis, pyelonephritis, and diarrhea, coughs, and vaginal yeast infection, is associated with an increased risk of epilepsy in childhood.
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