Yuelian Sun

Risk of Febrile Seizures and Epilepsy After Vaccination With Diphtheria, Tetanus, Acellular Pertussis, Inactivated Poliovirus, and Haemophilus Influenzae Type b

CONTEXT Vaccination with whole-cell pertussis vaccine carries an increased risk of febrile seizures, but whether this risk applies to the acellular pertussis vaccine is not known. In Denmark, acellular pertussis vaccine has been included in the combined diphtheria-tetanus toxoids-acellular pertussis-inactivated poliovirus-Haemophilus influenzae type b (DTaP-IPV-Hib) vaccine since September 2002. OBJECTIVE To estimate the risk of febrile seizures and epilepsy after DTaP-IPV-Hib vaccination given at 3, 5, and 12 months. DESIGN, SETTING, AND PARTICIPANTS A population-based cohort study of 378,834 children who were born in Denmark between January 1, 2003, and December 31, 2008, and followed up through December 31, 2009; and a self-controlled case series (SCCS) study based on children with febrile seizures during follow-up of the cohort. MAIN OUTCOME MEASURES Hazard ratio (HR) of febrile seizures within 0 to 7 days (0, 1-3, and 4-7 days) after each vaccination and HR of epilepsy after first vaccination in the cohort study. Relative incidence of febrile seizures within 0 to 7 days (0, 1-3, and 4-7 days) after each vaccination in the SCCS study. RESULTS A total of 7811 children were diagnosed with febrile seizures before 18 months, of whom 17 were diagnosed within 0 to 7 days after the first (incidence rate, 0.8 per 100,000 person-days), 32 children after the second (1.3 per 100,000 person-days), and 201 children after the third (8.5 per 100,000 person-days) vaccinations. Overall, children did not have higher risks of febrile seizures during the 0 to 7 days after the 3 vaccinations vs a reference cohort of children who were not within 0 to 7 days of vaccination. However, a higher risk of febrile seizures was found on the day of the first (HR, 6.02; 95% CI, 2.86-12.65) and on the day of the second (HR, 3.94; 95% CI, 2.18-7.10), but not on the day of the third vaccination (HR, 1.07; 95% CI, 0.73-1.57) vs the reference cohort. On the day of vaccination, 9 children were diagnosed with febrile seizures after the first (5.5 per 100,000 person-days), 12 children after the second (5.7 per 100,000 person-days), and 27 children after the third (13.1 per 100,000 person-days) vaccinations. The relative incidences from the SCCS study design were similar to the cohort study design. Within 7 years of follow-up, 131 unvaccinated children and 2117 vaccinated children were diagnosed with epilepsy, 813 diagnosed between 3 and 15 months (2.4 per 1000 person-years) and 1304 diagnosed later in life (1.3 per 1000 person-years). After vaccination, children had a lower risk of epilepsy between 3 and 15 months (HR, 0.63; 95% CI, 0.50-0.79) and a similar risk for epilepsy later in life (HR, 1.01; 95% CI, 0.66-1.56) vs unvaccinated children. CONCLUSIONS DTaP-IPV-Hib vaccination was associated with an increased risk of febrile seizures on the day of the first 2 vaccinations given at 3 and 5 months, although the absolute risk was small. Vaccination with DTaP-IPV-Hib was not associated with an increased risk of epilepsy.

Apgar Scores and Long-Term Risk of Epilepsy

Background: Low Apgar scores are associated with high risk of neonatal death, cerebral palsy, and mental retardation, but the association between Apgar scores and long-term risk of epilepsy remains unresolved. Methods: We carried out a population-based cohort study of 1,538,732 live newborns in Denmark between 1 January 1978 and 31 December 2002 by using national registers. The Apgar scores at 1 or 5 minutes were recorded by midwives following standardized procedures. We obtained information on epilepsy by linking the cohort with the National Hospital Register. Cohort members were followed from birth until onset of epilepsy, death, emigration, or 31 December 2002, whichever came first. Results: The incidence rate of epilepsy increased consistently with decreasing Apgar scores. The incidence rate of epilepsy was 628 per 100,000 person-years for those with 5-minute Apgar scores of 1 to 3 and 86 per 100,000 person-years for those with a score of 10; the resulting incidence rate ratio was 7.1 (95% confidence interval = 5.8–8.8). The incidence rate ratios of epilepsy associated with low Apgar scores were particularly high in early childhood but remained high into adulthood. The association did not change after excluding children with cerebral palsy, congenital malformations, or a parental history of epilepsy. Conclusions: Neonates with a suboptimal Apgar score have a higher risk of epilepsy that lasts into adult life. These findings suggest that prenatal or perinatal factors play a larger role in the etiology of epilepsy than has previously been recognized.

Prenatal exposure to maternal infections and epilepsy in childhood: A population-based cohort study.

OBJECTIVE. We estimated the association between prenatal exposure to maternal infections and the subsequent risk for epilepsy in childhood. 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.

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

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 > or = 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.

Risk of Cerebral Palsy and Childhood Epilepsy Related to Infections before or during Pregnancy

Background and Aim Maternal infections during pregnancy have been associated with several neurological disorders in the offspring. However, given the lack of specificity for both the exposures and the outcomes, other factors related to infection such as impaired maternal immune function may be involved in the causal pathway. If impaired maternal immune function plays a role, we would expect infection before pregnancy to be associated with these neurological outcomes. Methods/Principal Findings The study population included all first-born singletons in Denmark between January 1 1982 and December 31 2004. We identified women who had hospital-recorded infections within the 5 year period before pregnancy, and women who had hospital-recorded infections during pregnancy. We grouped infections into either infections of the genitourinary system, or any other infections. Cox models were used to estimate adjusted hazard ratios (aHRs) with 95% confidence interval (CI). Maternal infection of the genitourinary system during pregnancy was associated with an increased risk of cerebral palsy (aHR = 1.63, 95% CI: 1.34–1.98) and epilepsy (aHR = 1.27, 95% CI: 1.13–1.42) in the children, compared to children of women without infections during pregnancy. Among women without hospital-recorded infections during pregnancy, maternal infection before pregnancy was associated with an increased risk of epilepsy (aHR = 1.35, 95% CI: 1.21–1.50 for infections of the genitourinary system, and HR = 1.12, 95% CI: 1.03–1.22 for any other infections) and a slightly higher risk of cerebral palsy (aHR = 1.20, 95% CI: 0.96–1.49 for infections of the genitourinary system, and HR = 1.23, 95% CI: 1.06–1.43 for any other infections) in the children, compared to children of women without infections before (and during) pregnancy. Conclusions These findings indicate that the maternal immune system, maternal infections, or factors related to maternal immune function play a role in the observed associations between maternal infections before pregnancy and cerebral diseases in the offspring.

Prenatal exposure to elevated maternal body temperature and risk of epilepsy in childhood: a population‐based pregnancy cohort study

Elevated maternal body temperature during pregnancy is of clinical concern as side effects have been reported. We estimated the association between maternal fever and sauna bathing during pregnancy and risk of epilepsy in the offspring. We identified 86,810 liveborn singletons from the Danish National Birth Cohort (DNBC) and followed them for up to 9 years of age. Information on fever including number, timing, level, duration, and symptoms of each fever episodes was collected in two computer-assisted telephone interviews around 17 and 32 gestational weeks; information on maternal use of a sauna was collected in the latter interview, and information on epilepsy was obtained from the Danish National Hospital Register. We applied Cox regression models to estimate the incidence rate ratios (IRR) of epilepsy for children exposed to maternal fever and sauna bathing during pregnancy. Maternal sauna bathing during pregnancy was not associated with an increased risk of epilepsy. Maternal fever during pregnancy in general was not associated with an increased risk of epilepsy in the offspring [IRR = 1.01, 95% confidence interval (CI) 0.85, 1.19], and no dose-response pattern was found according to number, level and duration of fever. However we did find an increased risk of epilepsy among children exposed to at least 3 fever episodes (IRR = 1.88, 95% CI 1.19, 2.98), to maternal fever with symptoms in the urinary system (IRR = 4.86, 95% CI 1.56, 15.17), and to one-day maternal fever of 39.0-39.4°C (IRR = 2.79, 95% CI 1.60, 4.84). Our findings do not support a strong association between hyperthermia and epilepsy but the associations between underlying causes of fever, especially prenatal infections, call for more research.

Gestational age, birth weight, and risk for injuries in childhood.

Background: Some children experience more injuries than others due to personal or environmental risk factors, or to chance. Most injury studies have focused on proximal causes; few have examined the role of neonatal characteristics such as birth weight and gestational age. Methods: We carried out a population-based cohort study of 1,524,114 singletons born in Denmark between 1 January 1978 and 31 December 2004. We obtained information on gestational age, birth weight, and injury from the Danish Medical Birth Registry and the National Hospital Register. We followed participants up to age 29 years and estimated the incidence rate ratio (IRR) of hospitalization for injury, using Poisson regression models. Results: The risk of injury throughout childhood (mainly before 12 years of age) increased with decreasing gestational age and birth weight. The IRR of injury in the first 12 years of life was 4.2 (95% CI = 3.5-5.1), 2.3 (2.0-2.5), and 1.5 (1.3-1.6), respectively, for children born at gestational weeks 20-32, 33-36, and 37-38, compared with those born at gestational weeks 39-41. The IRR was 4.0 (3.4-4.6), 2.5 (2.1-2.8), and 1.4 (1.3-1.6) for children with a birth weight less than 2000 g, 2000-2499 g, and 2500-2999 g, compared with children of 3000-3999 g. Birth weight was also associated with increased risks of injury after adjusting for gestational age. Conclusions: Children born with adverse neonatal conditions have a marked increased risk of injury. This suggests an opportunity to identify children who may benefit from injury prevention. More research is needed to identify the causal pathways driving these associations.

Cancer risks in children with congenital malformations in the nervous and circulatory system—A population based cohort study

AIM We estimated the age and organ-specific cancer risk for children with a congenital malformation (CM) in the nervous or in the circulatory system. METHODS We identified 1,709,456 live born singletons in Denmark between 1 January 1977 and 31 December 2007 and excluded children with chromosomal birth defects. Information on CMs was obtained from the Danish National Hospital Register. Information on cancer occurrence was obtained from the Danish Cancer Registry. We applied Cox proportional hazards regression model to estimate hazard ratios (HR) for cancer. Children entered into the CM cohort on the day of birth regardless of when the CM was diagnosed or on the day of CM diagnosis in an alternative analysis. RESULTS Overall, 4484 (0.26%) and 24,643 (1.44%) children were diagnosed with a CM in the nervous and in the circulatory system, respectively. Compared with children without any CM, children with a CM in the nervous system had a 5.97 fold (95%CI [confidence interval]: 4.66-7.64) higher risk of cancer, including cancer in the central nervous system (HR=18.84, 95%CI: 12.67-28.01), in the mesothelial and soft tissue (HR=15.64, 95%CI: 7.99-30.60), in the skin (HR=4.91, 95%CI: 2.19-11.0). The associations were stronger early in life. Children with a CM in the circulatory system had a 2.64 fold (95%CI: 2.21-3.16) higher risk of cancer, including cancer in the lymphatic and haematopoietic tissues (HR=3.22, 95%CI: 2.43-4.27) and cancer in the CNS (HR=2.40, 95%CI: 1.43-4.02). Some of these associations were weaker in the alternative analysis. Children with subtypes of CM in the two systems showed a higher cancer risk. CONCLUSIONS Children who were diagnosed with a CM in the nervous system had a substantially higher cancer risk especially early in life. Children diagnosed with a CM in the circulatory system had a moderately higher cancer risk.

Prenatal exposure to antidepressants and risk of epilepsy in childhood

This study aimed to estimate the association between prenatal exposure to antidepressants and risk of epilepsy in childhood, taking maternal depression into account.

Maternal Use of Cystitis Medication and Childhood Epilepsy in a Danish Population‐based Cohort

BACKGROUND Maternal infections during pregnancy have been associated with an increased risk for neurological outcomes in the child, including epilepsy. We examined cystitis antibiotics commonly used during pregnancy, as a marker of cystitis, and the risk of childhood epilepsy in a population-based cohort in Denmark. METHODS We examined all liveborn singletons born in Denmark between January 1996 and September 2004, identified from the Danish National Birth Registry. Epilepsy diagnoses were obtained from the Danish National Hospital Register and maternal antibiotic use from the National Register of Medicinal Product Statistics. Cystitis antibiotics consisted of pivmecillinam, sulphamethizole and nitrofurantoin. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated with Cox proportional hazard regression models. RESULTS The study followed 447629 singletons for up to 9.9 years and identified 2848 children diagnosed with epilepsy. We found slightly increased risks of epilepsy in children whose mothers had redeemed prescriptions during pregnancy for pivmecillinam HR=1.2 [95% CI 1.0, 1.4], sulphamethizole HR=1.2 [95% CI 1.1, 1.4] or nitrofurantoin HR=1.1 [95% CI 0.8, 1.5], compared with those unexposed. Among mothers with multiple redeemed prescriptions during pregnancy, adjusted HR were for pivmecillinam HR=1.3 [95% CI 1.1, 1.5], sulphamethizole HR=1.3 [95% CI 1.1, 1.5] and nitrofurantoin HR=1.3 [95% CI 1.0, 1.8]. CONCLUSIONS Similar magnitudes of associations between chemically different drugs, used almost exclusively to treat cystitis, may suggest an impact of maternal infection on the fetal brain. However, direct drug effects or confounding factors are also possible explanations.