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OBJECTIVE: Prenatal exposure to the antiseizure medication (ASM) valproate is associated with an increased risk of congenital malformations, but warnings against the use of valproate in pregnancy were not issued until 2009. The objective was to study how early administrative health registers could have identified the teratogenic risk associated with valproate.METHODS: This was a population-based cohort study of individual-linked data from Danish health care and socioeconomic registers including children born in Denmark between January 1, 1997 and December 31, 2014. Information on ASM use, including valproate, in pregnancy was obtained from the Danish National Prescription Registry. Children identified with major congenital malformations from the Danish National Patient Register and the Danish Register of Causes of Death were included. Using logistic regression models, we estimated odds ratios (ORs) and 95% confidence intervals (CIs) for major congenital malformations during the first year of life in children with and without prenatal exposure to ASMs adjusted for potential confounders.RESULTS: Among the 895 507 children (males, 51.3%), 31 790 (3.6%) were diagnosed with a major congenital malformation in the first year of life. In the analyses including children born in 1997, the risk of major congenital malformations among children prenatally exposed to valproate compared with children not exposed to ASMs was increased by a fully adjusted OR (aOR) of 3.95 (95% CI = 1.65-9.47). With the addition of data from the following years, the teratogenic effect of valproate was further substantiated, as the precision of the estimate improved (1997-2014: aOR = 2.44, 95% CI = 1.80-3.30).SIGNIFICANCE: Using Danish health care data, we were able to identify a teratogenic risk associated with prenatal valproate exposure in children born in 1997, which is much earlier than prospective clinical cohorts. Health registry data represent an important tool for early identification of risk associated with drugs in pregnancy.

Importance: Concerns exist about long-term neurodevelopmental consequences of prenatal exposure to antidepressants.Objective: To evaluate whether maternal prescription fill for antidepressants in pregnancy was associated with performance in standardized tests among Danish schoolchildren.Design, Setting, and Participants: Population-based retrospective cohort study of children born in Denmark between January 1, 1997, and December 31, 2009, attending public primary and lower secondary school. The children included had completed a language or mathematics test as part of the Danish National Test Program between January 1, 2010, and December 31, 2018. The age range of the eligible schoolchildren was 7 to 17 years.Exposures: Maternal prescription fill for antidepressants during pregnancy, obtained from the Danish Prescription Register.Main Outcomes and Measures: The difference in standardized scores between children with and without maternal prescription fill for antidepressants in mathematics and language tests (scale, 1-100; higher scores indicate better test results) was estimated using linear regression models, adjusted for relevant confounders. Ten sensitivity analyses were performed, including a sibling-controlled analysis.Results: Among the 575 369 children included (51.1% males), 10 198 (1.8%) were born to mothers filling an antidepressant prescription during pregnancy. The mean (SD) age of children at the time of testing spanned from 8.9 (0.4) years in grade 2 to 14.9 (0.4) years in grade 8. Maternal prescription fill for antidepressants was significantly associated with a poorer performance in mathematics (mean test scores for the group exposed to maternal antidepressant fill: 52.1 [95% CI, 51.7-52.6] and for the group not exposed to maternal antidepressant fill: 57.4 [95% CI, 57.3-57.4]; adjusted difference, -2.2 [95% CI, -2.7 to -1.6]), but not in language (mean test scores for the exposed group: 53.4 [95% CI, 53.1-53.7] and for the not exposed group: 56.6 [95% CI, 56.5-56.6]; adjusted difference, -0.1 [95% CI, -0.6 to 0.3]). In the sibling-controlled analysis, the adjusted difference in mathematics (mean scores for the exposed group: 53.5 [95% CI, 52.7-54.3] and for the not exposed group: 59.0 [95% CI, 58.9-59.1]) was -2.8 (95% CI, -4.5 to -1.2) and in language (mean test scores for the exposed group: 53.9 [95% CI, 53.2-54.6] and for the not exposed group: 56.6 [95% CI, 56.5-56.7]) was -0.3 (95% CI, -1.9 to 1.2).Conclusions and Relevance: In this study of public schoolchildren in Denmark, children whose mothers had filled prescriptions for antidepressants during pregnancy, compared with children whose mothers did not fill prescriptions for antidepressants during pregnancy, had a 2-point lower standardized test score in mathematics, a difference that was statistically significant, but had no significant difference in language test scores. The magnitude of the difference in the mathematics test score was small and of uncertain clinical importance, and the findings must be weighed against the benefits of treating maternal depression during pregnancy.

Purpose: We estimated the association between maternal antidepressant (AD) use in early pregnancy and risk of congenital heart defects. Methods: We applied a case-time-control design with the aim of controlling for confounding from time-invariant factors and compared the results of the design to results from a cohort design in a population of 792 685 singletons born alive in Denmark during 1995-2008. In the case-time-control design, we identified children diagnosed with a congenital heart defect in the first 5 years of life (cases) and compared maternal AD use in the risk period (the first 3 months of pregnancy) and the reference period (gestational months 5-7). A nondiseased control group was included to adjust for time trends of exposure. In the cohort design, we identified children whose mothers redeemed at least one AD prescription in the first 3 months of pregnancy (the exposed) and two other groups including the unexposed children with maternal AD prescriptions in the 12 months before pregnancy. We applied conditional logistic regression and logistic regression to compute odds ratios (ORs) and 95% confidence intervals (CIs). Results: The case-time-control OR for any congenital heart defect was 1.03 (95% CI, 0.61-1.73), which was similar to the OR (1.09, 95% CI, 0.88-1.35) from the cohort design when we compared the exposed children with the unexposed children with maternal AD use before pregnancy. Conclusions: The case-time-control design provided results similar to the cohort design when the cohort design had a better confounder control strategy. We discussed the strengths and drawbacks of case-time-control design.

This cohort study evaluates risk of intellectual disability and delayed childhood milestones among children exposed prenatally to valproate and other antiepileptic drugs., Key Points Question Is prenatal exposure to valproate or other antiepileptic drugs associated with increased risk of intellectual disability and delayed development in childhood milestones? Findings In this cohort study of 913 302 Danish children, prenatal valproate exposure was associated with 4.5-fold increased risk of intellectual disability and 6-fold increased risk of combined outcome of intellectual disability and delayed childhood milestones compared with children with no prenatal valproate exposure. Other antiepileptic drugs, including carbamazepine, clonazepam, and oxcarbazepine, were also found to be associated with increased risk of intellectual disability. Meaning These findings add to the evidence for risk in the use of valproate among pregnant women and all women of childbearing potential and suggest risks in the use of other antiepileptic drugs by these populations., Importance There is concern about neurodevelopmental outcomes associated with prenatal exposure to valproate and other antiepileptic drugs (AEDs) among children of mothers with or without epilepsy. Objective To study the risk of intellectual disability and delayed development in childhood milestones among children of women who used valproate or other AEDs during pregnancy. Design, Setting, and Participants This population-based cohort study analyzed information on use of AEDs from the Danish National Prescription Registry and register diagnoses from the Danish Psychiatric Central Research Register and Danish National Patient Registry. The study included all live-born singletons in Denmark from January 1, 1997, to December 31, 2011. Data were analyzed in April 2020. Exposures Prenatal exposure to maternal valproate and other AEDs. Main Outcomes and Measures The main measures were adjusted Cox regression estimates of hazard ratios (aHRs) for intellectual disability and a combined outcome of intellectual disability with delayed childhood milestones. Results A total of 913 302 children (468 708 [51.3%] boys; mean [SD] age, 10.3 [4.4] years and median [interquartile range] age, 10.1 [6.5-14.0] years at final follow-up) were identified and contributed more than 10.2 million person-years of observation, including 580 children exposed to valproate (302 [51.3%] boys). At end of follow-up, 6958 children (0.8%) were identified as having intellectual disability and 14 967 children (1.6%) were identified as having intellectual disability with delayed childhood milestones. Compared with offspring not exposed to valproate prenatally, offspring of women who used valproate during pregnancy had increased risk of intellectual disability (aHR, 4.48; 95% CI, 2.97-6.76) and intellectual disability with delayed childhood milestones (aHR, 6.07; 95% CI, 4.67-7.89). Among mothers with epilepsy, offspring exposed prenatally to valproate had increased risk of intellectual disability (aHR, 1.95; 95% CI, 1.21-3.14) and intellectual disability with delayed childhood milestones (aHR, 3.07; 95% CI, 2.24-4.20) compared with offspring without prenatal exposure. Compared with offspring without prenatal exposure to AEDs, increased risk of intellectual disability was identified in children with prenatal exposure to maternal monotherapy use of carbamazepine (aHR, 3.84; 95% CI, 2.32-6.38), clonazepam (aHR, 2.41; 95% CI, 1.09-5.35), and oxcarbazepine (aHR, 3.70; 95% CI, 2.11-6.51) but not lamotrigine (aHR, 1.33; 95% CI, 0.71-2.48). Conclusions and Relevance These findings suggest that prenatal exposure to valproate was associated with increased risk of intellectual disability and delayed childhood milestones. Statistically significant associations were also found for prenatal exposure to other AEDs. These findings suggest that women of childbearing potential may need to be counseled on use of AEDs.

Purpose Antidepressants are the mainstay of pharmacological treatment for nonpsychotic mental disorders in the perinatal period. However, little is known about the indications for antidepressant use during pregnancy. We aimed to examine the treatment indications of antidepressant prescriptions redeemed by pregnant women and to investigate whether treatment indication patterns changed over time. Methods We conducted a population-based descriptive study using Danish national registers. We identified pregnancies resulting in live births between 2006 and 2016 from the Medical Birth Registry. We linked them to the National Prescription Registry to extract information on antidepressant prescriptions during pregnancy. We used generalized estimating equations to examine whether the indication patterns of antidepressants changed over time. Results A total of 47 093 antidepressant prescriptions associated with 17 170 pregnancies were identified. Overall, 82.3% of pregnancies received antidepressant prescriptions for depression, including 9.2% of pregnancies affected by comorbid indications, mainly anxiety disorders. In addition, 11.5% of pregnancies received prescribed antidepressants for anxiety disorders only, 3.8% for insomnia only, 0.5% for anxiety and insomnia, and 1.9% for other disorders. There was a small decrease in the percentage of antidepressant prescriptions for depression from 2006 to 2016, with an adjusted 1-year risk difference of -0.4% (95% confidence interval [CI], -0.7% to -0.1%), while the percentage for anxiety disorders increased, and the adjusted 1-year risk difference was 0.9% (95% CI, 0.7% to 1.1%). Conclusion The majority of antidepressant prescriptions in pregnancy are for depression treatment, which suggests that antidepressant prescription during pregnancy may be a suitable proxy for a depression diagnosis.

BACKGROUND: There is a complex interaction between female and male sex hormones and the risk of epilepsy. Whether prenatal exposure to higher levels of sex hormones affects the development of epilepsy in childhood or later in life is not well known. The sex hormone environment of fetuses may be affected by the sex of the co-twin. We estimated the risk of epilepsy for twins with an opposite-sex (OS) co-twin compared with twins with a same-sex (SS) co-twin.METHODS: From the Danish Twin Registry, we identified OS female twins (n = 11,078), SS female twins (n = 19,186), OS male twins (n = 11,080), and SS male twins (n = 20,207) born between 1977 and 2009. The SS twins include monozygotic twins, dizygotic twins, and twins with unknown zygosity. These children were followed up from day 29 after birth until diagnosis of epilepsy, death, emigration, or end of follow-up (31 December 2011) whichever came first. Information on diagnosis of epilepsy was obtained from the Danish National Patient Registry. We calculated hazard ratios (HRs) and 95% confidence intervals (CIs) for epilepsy in the OS twins using a Cox proportional hazards regression model compared with the SS twins. To account for the correlation of twins from the same mother when estimating standard errors, we used the cluster option in Stata.RESULTS: We identified 152 OS female twins, 282 SS female twins, 162 OS male twins, and 335 SS male twins diagnosed with epilepsy corresponding to an incidence rate of 9.9 and 9.7 per 10,000 person years for the OS and SS female twins, and 10.6 and 10.9 per 10,000 person years for the OS and SS male twins, respectively. We found a similar risk of epilepsy among the OS and SS female twins [HR = 1.01; 95% CI 0.83-1.24] as well as among the OS and SS male twins [HR = 0.94; 95% CI 0.78-1.14] CONCLUSIONS: In this population-based study of Danish twins, we did not find difference in the risk of epilepsy between twins with an OS co-twin and twins with a SS co-twin. This applied to both female and male twins. The study therefore does not support the hypothesis that subtle hormone difference in fetal life due to co-twin may play a role in the development of epilepsy later in life.

Importance: Febrile seizures occur in 2% to 5% of children between the ages of 3 months and 5 years. Many affected children experience recurrent febrile seizures. However, little is known about the association between recurrent febrile seizures and subsequent prognosis.Objective: To estimate the risk of recurrent febrile seizures and whether there is an association over long-term follow-up between recurrent febrile seizures and epilepsy, psychiatric disorders, and death in a large, nationwide, population-based cohort in Denmark.Design, Setting, and Participants: This population-based cohort study evaluated data from all singleton children born in Denmark between January 1, 1977, and December 31, 2011, who were identified through the Danish Civil Registration System. Children born in Denmark who were alive and residing in Denmark at age 3 months were included (N = 2 103 232). The study was conducted from September 1, 2017, to June 1, 2019.Exposures: Hospital contacts with children who developed febrile seizures between age 3 months and 5 years.Main Outcomes and Measures: Children diagnosed with epilepsy were identified in the Danish National Patient Register and children diagnosed with psychiatric disorders were identified in the Psychiatric Central Research Register. Competing risk regression and Cox proportional hazards regression were used to estimate the cumulative and relative risk of febrile seizures, recurrent febrile seizures, epilepsy, psychiatric disorders, and death.Results: Of the 2 103 232 children (1 024 049 [48.7%] girls) in the study population, a total of 75 593 children (3.6%) were diagnosed with a first febrile seizure between 1977 and 2016. Febrile seizures were more common in boys (3.9%; 95% CI, 3.9%-4.0%) than in girls (3.3%; 95% CI, 3.2%-3.3%), corresponding to a 21% relative risk difference (hazard ratio, 1.21; 95% CI, 1.19-1.22). However, the risks of recurrent febrile seizures, epilepsy, psychiatric disorders, and death were similar in boys and girls. The risk of (recurrent) febrile seizures increased with the number of febrile seizures: 3.6% at birth, 22.7% (95% CI, 22.4%-23.0%) after the first febrile seizure, 35.6% (95% CI, (34.9%-36.3%) after the second febrile seizure, and 43.5% (95% CI, (42.3%-44.7%) after the third febrile seizure. The risk of epilepsy increased progressively with the number of hospital admissions with febrile seizures. The 30-year cumulative risk of epilepsy was 2.2% (95% CI, (2.1%-2.2%) at birth compared with 15.8% (95% CI, 14.6%-16.9%) after the third febrile seizure, while the corresponding estimates for risk of psychiatric disorders were 17.2% (95% CI, 17.2%-17.3%) at birth and 29.1% (95% CI, 27.2%-31.0%) after the third febrile seizure. Mortality was increased among children with recurrent febrile seizures (1.0%; 95% CI, 0.9%-1.0% at birth vs 1.9%; 95% CI, 1.4%-2.7% after the third febrile seizure), although this risk was associated primarily with children who later developed epilepsy.Conclusions and Relevance: A history of recurrent febrile seizures appears to be associated with a risk of epilepsy and psychiatric disorders, but increased mortality was found only in individuals who later developed epilepsy.

OBJECTIVE: The objective of this study was to investigate the accident-related mortality among people younger than 55 years of age with epilepsy compared with the general population and to study how psychiatric comorbidity influences this risk.METHODS: This is a population-based cohort study of individuals born in Denmark between 1960 and 2015 (n = 3, 665 616). Persons diagnosed with epilepsy and psychiatric disorders were identified in the Danish National Patient Register and the Danish Central Psychiatric Central Register. We estimated the hazard ratio (HR) with 95% confidence intervals (CIs) of accidental death in people with epilepsy compared with persons without epilepsy.RESULTS: We identified 61 330 persons (1.7%) diagnosed with epilepsy. Median age at end of follow-up was 27.8 years. In people with epilepsy, 5253 died during follow-up, 480 (9%) of whom died from accidents. Among people without epilepsy, 52 588 died during follow-up, of whom 1280 (2.4%) died from accidents. People with epilepsy had a 3.7-fold (95% CI 3.4-4.1) increased risk of accidental death compared with persons without epilepsy. When we adjusted for psychiatric disorders, the risk remained significantly elevated in people with epilepsy compared to people without epilepsy (adjusted HR [aHR] 2.44, 95% CI 2.22-2.69). When stratifying the analyses on epilepsy and psychiatric disorders, people with epilepsy and psychiatric disorders had an aHR of 4.95 (95% CI 3.82-6.41) when compared with persons without epilepsy and psychiatric disorders.SIGNIFICANCE: The risk of accidental death was increased in people with epilepsy and was particularly high among people with epilepsy with psychiatric comorbidity. The findings highlight the need for awareness and prevention strategies in people with epilepsy, especially in people with comorbid psychiatric disorders.

Introduction Factors that influence antidepressant (AD) prescription and use during pregnancy are multiple including, in particular, the balance between the potential risk of untreated depression and the potential risk of AD treatment. Surveillance of temporal trends of AD use might identify areas requiring further research. We studied the use of ADs before, during, and after pregnancy using national data across two decades in Denmark. Methods We included 1,232,233 pregnancies leading to live birth in Denmark between 1 January 1997 and 31 December 2016. Information on redemption of AD prescriptions was obtained from the Danish National Prescription Register. Results We identified 29,504 (2.4%) pregnancies having at least one AD prescription (96,232 AD prescriptions) during pregnancy. The majority redeemed more than one prescription (69.7%) often for a single kind of AD (83.5%), and in 94% of the AD‐exposed pregnancies, the estimated duration of treatment was 1 month or longer. Prescription of ADs during pregnancy increased steadily from 0.4% in 1997 to 4.6% in 2011, but decreased thereafter to 3.1% in 2016. The proportion of pregnancies with ADs in 2011 was 6.05‐fold higher than that in 1997. The temporal trends in AD prescription in the years before and after pregnancy were similar to the trend during pregnancy. The decreasing use of ADs during pregnancy after 2011 was mainly driven by a decrease in the use of selective serotonin reuptake inhibitors (SSRIs), especially citalopram, the main type of SSRIs used in Denmark. Conclusion Prescription of ADs during pregnancy in Denmark increased steadily from 1997 to 2011 but decreased sharply thereafter. More research is needed to show whether the same trend exists in other populations, like women of reproductive age, men of reproductive age, and old people, and other countries. We also need to find explanation for the decreasing trend in recent years and potential risk for untreated depression., The proportion of pregnant women who redeemed antidepressants (AD) during pregnancy increased sixfold from 1997 to 2011, but decreased sharply thereafter—similar trends were found before and after pregnancy. The decrease in the use of AD after 2011 was mainly due to a decrease in the prescribing of serotonin reuptake inhibitors (SSRIs) and in particular citalopram, the main type of SSRI used in Denmark.

Purpose This study aimed to estimate the association between prenatal exposure to antidepressants and risk of epilepsy in childhood, taking maternal depression into account. Methods We conducted a population-based cohort study including all Danish singletons born alive between 1997 and 2008 (n = 734 237). Information on antidepressant medication and diagnosis of depression and epilepsy was obtained from Danish National Registers. The exposed group comprised children of mothers who used antidepressants from 30 days before pregnancy until the date of birth. The reference group comprised children of mothers who used no antidepressants from 6 months before pregnancy to birth. We estimated the hazard ratios (HR) of epilepsy and 95% confidence intervals (CI) using Cox proportional hazard models. Results We identified 12 438 (1.7%) children exposed to antidepressants during pregnancy (including 30 days before pregnancy) and 5829 (0.8%) children diagnosed with epilepsy in the follow-up time (mean: 6.7 years). Children exposed to antidepressants during pregnancy had a 27% higher risk of epilepsy (aHR: 1.27; 95%CI: 1.05–1.54) than children in the reference group. The estimate of this association was 1.71 (95%CI: 1.10–2.66) if their mothers also had a registry-based hospital diagnosis of depression in the 6 months before pregnancy or during pregnancy and 1.14 (95%CI: 0.91–1.43) if their mothers had no registry-based hospital diagnosis of depression. Children of mothers who used antidepressants from 2 to 6 months before pregnancy (but not during pregnancy) had an increased risk of epilepsy (aHR: 1.36; 95%CI: 1.07–1.73). Conclusions Antidepressant use during pregnancy was associated with a higher risk of epilepsy among children whose mothers had also a registry-based hospital diagnosis of depression during pregnancy. Copyright © 2016 John Wiley & Sons, Ltd.

China has gone through a comprehensive health care insurance reform since 2003 and achieved universal health insurance coverage in 2011. The new health care insurance system provides China with a huge opportunity for the development of health care and medical research when its rich medical resources are fully unfolded. In this study, we review the Chinese health care system and its implication for medical research, especially within clinical epidemiology. First, we briefly review the population register system, the distribution of the urban and rural population in China, and the development of the Chinese health care system after 1949. In the following sections, we describe the current Chinese health care delivery system and the current health insurance system. We then focus on the construction of the Chinese health information system as well as several existing registers and research projects on health data. Finally, we discuss the opportunities and challenges of the health care system in regard to clinical epidemiology research. China now has three main insurance schemes. The Urban Employee Basic Medical Insurance (UEBMI) covers urban employees and retired employees. The Urban Residence Basic Medical Insurance (URBMI) covers urban residents, including children, students, elderly people without previous employment, and unemployed people. The New Rural Cooperative Medical Scheme (NRCMS) covers rural residents. The Chinese Government has made efforts to build up health information data, including electronic medical records. The establishment of universal health care insurance with linkage to medical records will provide potentially huge research opportunities in the future. However, constructing a complete register system at a nationwide level is challenging. In the future, China will demand increased capacity of researchers and data managers, in particular within clinical epidemiology, to explore the rich resources.

Purpose Studies on the safety of drugs used during pregnancy are necessary and important but prone to bias. Using cases as their own controls can reduce bias. We used a case-crossover design and a case-time-control design to estimate the risk of congenital malformation (CM) for children born to mothers who redeemed a trimethoprim prescription shortly before pregnancy. Methods The study was based on all live born singletons (N = 685 600) in Denmark whose mothers had available information on prescriptions in the Danish National Prescription Registry between 1996 and 2008. We defined 1–3 months before pregnancy as a potential risk period and 13–15 months before pregnancy as a reference period. Two other reference periods were used (7–9 months before pregnancy and months 4–6 of pregnancy). The case-crossover design is dependent on the assumption of a stable trimethoprim prescription over the study period in the source population. To estimate the trend of trimethoprim prescriptions, we used a control group comprising children without CMs. Results Both study designs showed children had a higher risk of overall CM [odds ratio of 1.66, 95% confidence interval (CI): 1.10–2.53 and 1.50, 95%CI: 0.66–3.38, respectively] if their mothers had a trimethoprim prescription in the 3 months before pregnancy and subtypes of CM for example in the musculoskeletal system, which were consistent to the previous findings from a cohort study. Conclusions This study corroborates that trimethoprim is a potential teratogen when used 3 months before pregnancy and demonstrates the value of case-only approaches for studying, for example, adverse effects of antibiotics in reproductive epidemiology. Copyright © 2014 John Wiley & Sons, Ltd.

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.

Cancer risk in parents may be related to congenital malformations (CMs) in their children if they share genetic susceptibility or environmental exposure that may be teratogenic and carcinogenic. We conducted a population-based cohort study based on Danish register data. We identified 795,607 mothers and 781,424 fathers who had all their children between 1977 and 2007 in Denmark. Information on CM was obtained from the Danish Hospital Registry and information on cancer was obtained from the Danish Cancer Registry. Parents were followed from the birth of their first child until the diagnosis of cancer, death, emigration, or December 31, 2007. We used Cox regression models to estimate hazard ratios (HRs) for cancer including cancer in specific organs in mothers and fathers. Overall, 75,701 (9.5%) mothers and 72,724 (9.3%) fathers had at least one child diagnosed with CMs within the first year of life. Neither mothers (HR = 1.04; 95% CI: 0.99–1.04) nor fathers (HR = 1.03; 95% CI: 0.98–1.09) who had a child with a CM had a higher overall risk of cancer. Mothers (HR = 0.76, 95% CI: 0.58–1.00) or fathers (HR = 0.89, 95% CI: 0.66–1.19) who had a child with a chromosomal malformation had a lower overall cancer risk. The findings also showed a higher risk for some specific types of cancer in parents who had children with a CM in the specific system. Some, or perhaps all, of these findings may be due to chance caused by multiple comparisons. We present all results on paper or online to provide clues for further research and to avoid publication bias.

Purpose Cancer and birth defects cluster in families more often than expected by chance, but the reasons are neither well known nor well studied. Methods From singletons born alive in Denmark between 1 January 1977 and 31 December 2007, we identified children who had no congenital malformations but had a full or half sibling with a congenital malformation (CM) diagnosed in the first year of life; this constituted the exposed group, while children whose siblings had no such condition constituted a reference group. We estimated cancer risks for children who had a full sibling or a half sibling with a CM using a Cox proportional hazards regression model. To control for confounding related to change of family structure, we estimated cancer risks for children from core families and children from broken families separately. Children were followed from birth up to 30 years of age (median follow-up 13.6 years). We obtained information on CMs and cancer from the Danish National Hospital Register and the Danish Cancer Registry. Results We identified 991,454 (78%) children from core families with 53,995 children who had a full sibling with a CM and 277,773 (22%) children from broken families with 7200 children who had a full sibling with a CM and 6194 children who had a half sibling with a CM. Children who had a full sibling with a CM from both core and broken families showed, in general, no increased cancer risk compared with children whose siblings had no CM, except in the case of children who had a full sibling with a CM in the nervous system (HR = 2.61, 95%CI:1.60–4.27) or in the eye, ear, face, or neck (HR = 2.47, 95%CI: 1.46–4.18). Children who had a half sibling with a CM seemed to have a higher cancer risk in early adulthood (HR = 1.87, 95%CI: 0.98–3.56). Conclusions Children who had a full sibling with a CM had no increased risk of cancer except for those who had a full sibling with a CM in the nervous system or in the eye, ear, face or neck. Children with a half-sibling with a CM tended to have an increased cancer risk in early adulthood, perhaps a result of chance. This study should be replicated using other data sources.

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 447 629 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.

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.

Depression forekommer ofte efter en kræftdiagnose og forbindes med øget mortalitet. Det er dog uvist, om depression i perioden før en kræftdiagnose også påvirker mortaliteten. Dette studie undersøger mortaliteten hos patienter, som blev behandlet med antidepressiv medicin før en kræftdiagnose. Resultaterne viser, at over 33.000 patienter (16,4 %) indløste mindst en recept med antidepressiv medicin i løbet af de seneste tre år før en kræftdiagnose. Heraf fik knap 22.000 (10.8 %) af disse patienter stadig medicinen på tidspunktet for kræftdiagnosen. For aktuelle brugere sås en 32 % højere 1-årsmortalitet end for ikke-brugere. Denne stigning gjaldt særlig patienter, som påbegyndte behandling med antidepressiv medicin inden for de seneste fire måneder før kræftdiagnosen, mens der ikke sås en øget risiko for tidligere brugere. Ligeledes sås en 22 % højere 5-årsmortalitet for de patienter, der overlevede det første år efter kræftdiagnosen. Konklusionen er, at påbegyndelse af behandling med antidepressiv medicin før en kræftdiagnose er forholdsvis hyppig, og at denne behandling forbindes med øget mortalitet. Studiet er gennemført som et populationsbaseret kohortestudie og omfatter data fra over 200.000 danskere, som blev diagnosticeret med kræft i perioden 2003-2010. BACKGROUND: Depression is common after a cancer diagnosis and is associated with an increased mortality, but it is unclear whether depression occurring before the cancer diagnosis affects cancer mortality. We aimed to study cancer mortality of people treated with antidepressants before cancer diagnosis.METHODS AND FINDINGS: We conducted a population based cohort study of all adults diagnosed with cancer between January 2003 and December 2010 in Denmark (N = 201,662). We obtained information on cancer from the Danish Cancer Registry, on the day of death from the Danish Civil Registry, and on redeemed antidepressants from the Danish National Prescription Registry. Current users of antidepressants were defined as those who redeemed the latest prescription of antidepressant 0-4 months before cancer diagnosis (irrespective of earlier prescriptions), and former users as those who redeemed the latest prescription five or more months before cancer diagnosis. We estimated an all-cause one-year mortality rate ratio (MRR) and a conditional five-year MRR for patients who survived the first year after cancer diagnosis and confidence interval (CI) using a Cox proportional hazards regression model. Overall, 33,111 (16.4%) patients redeemed at least one antidepressant prescription in the three years before cancer diagnosis of whom 21,851 (10.8%) were current users at the time of cancer diagnosis. Current antidepressant users had a 32% higher one-year mortality (MRR = 1.32, 95% CI: 1.29-1.35) and a 22% higher conditional five-year mortality (MRR = 1.22, 95% CI: 1.17-1.26) if patients survived the first year after the cancer diagnosis than patients not redeeming antidepressants. The one-year mortality was particularly high for patients who initiated antidepressant treatment within four months before cancer diagnosis (MRR = 1.54, 95% CI: 1.47-1.61). Former users had no increased cancer mortality.CONCLUSIONS: Initiation of antidepressive treatment prior to cancer diagnosis is common and is associated with an increased mortality.

Aim: To assess whether exposure to computers harms the semen quality of healthy young men. Methods: A total of 178 subjects were recruited from two maternity and children healthcare centers in Shanghai, 91 with a history of exposure to computers (i.e., exposure for 20 h or more per week in the last 2 years) and 87 persons to act as control (no or little exposure to computers). Data on the history of exposure to computers and other characteristics were obtained by means of a structured questionnaire interview. Semen samples were collected by masturbation in the place where the semen samples were analyzed. Results: No differences in the distribution of the semen parameters (semen volume, sperm density, percentage of progressive sperm, sperm viability and percentage of normal form sperm) were found between the exposed group and the control group. Exposure to computers was not found to be a risk factor for inferior semen quality after adjusting for potential confounders, including abstinence days, testicle size, occupation, history of exposure to toxic substances. Conclusion: The present study did not find that healthy men exposed to computers had inferior semen quality. (Asian J Androl 2005 Sep; 7: 263–266)

Several epidemiologic studies show associations between mother's infections during pregnancy and an increased risk of mental and neurological disorders in the offspring. Such associations could be due to the direct or indirect effects of infectious agents, including immune responses to infectious agents that display molecular mimicry with host antigens. We measured a range of antigen-specific maternal IgG antibodies to examine if any were associated with risk for childhood epilepsy in offspring.We used a case-cohort design within the Danish National Birth Cohort (DNBC) to examine maternal IgG antibodies to 25 microbial and tissue antigens during pregnancy and their association with the risk of epilepsy in offspring. The source population of this study was 68,250 live born singletons with up to 10 years of follow up. We randomly identified a sample of 282 children as a subcohort and included 275 children with a verified diagnosis of epilepsy as cases. Maternal antibodies were categorized into 6 groups (50, 50-59, 60-69, 70-79, 80-89, ≥90 percentile) according to the level in the subcohort. We used a Prentice-weighted Cox regression model to estimate the hazard ratio (HR) and 95% confidence interval (CI) for epilepsy according to measured antibodies.Higher levels of maternal antibodies against herpes simples virus type 1 (anti-HSV1) were associated with a slightly higher risk of childhood epilepsy (HR for trend=1.09, 95% CI: 0.99-1.21), while higher levels of maternal antibodies against pneumococcal polysaccharide 18 (anti-PnPS18) were associated with a lower risk of childhood epilepsy (HR for trend=0.90, 95% CI: 0.81-1.01). Among the subtypes, a significantly higher risk associated with anti-HSV1 antibodies was seen for childhood absence epilepsy (HR for trend=2.08, 95% CI: 1.12-3.85) and for epileptic encephalopathies (HR for trend=1.49, 95% CI: 1.01-2.22). The significantly lower risk associated with anti-PnPS18 antibodies was observed for infantile spasms (HR for trend=0.47, 95% CI: 0.27-0.83).Maternal anti-HSV1and anti-PnPS18 antibodies during pregnancy may be associated with the risk of epilepsy in offspring, but any potential etiologic and preventative implications of these associations warrant further exploration.

Author(s): Wu, Chun S; Pedersen, Lars H; Miller, Jessica E; Sun, Yuelian; Streja, Elani; Uldall, Peter; Olsen, Jorn | Abstract: Background and aimMaternal 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 findingsThe 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.ConclusionsThese 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.

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.

BACKGROUND: Term birth is a gestational age from 259 days to 293 days. However trends in mortality according to gestational ages in days have not yet been described in this time period.METHODS AND FINDINGS: Based on nation-wide registries, we conducted a population-based cohort study among all children born at term in Denmark from 1997 to 2004 to estimate differences in mortality across gestational ages in days among singletons born at term. We studied early-neonatal mortality, neonatal mortality, infant mortality, and five-year mortality. Children were followed from birth up to the last day of the defined mortality period or December 31, 2009. A total of 360,375 singletons born between 259 and 293 days of gestation were included in the study. Mortality decreased with increasing gestational age in days and the highest mortality was observed among children born at 37 week of gestation. A similar pattern was observed when analyses were restricted to children born to by mothers without pregnancy complications.CONCLUSIONS: This study demonstrates heterogeneity in mortality rates even among singletons born at term. The highest mortality was observed among children born 37 weeks of gestation, which call for cautions when inducing labor in term pregnancies just reaching 37 weeks of gestation. The findings support that 37 weeks of gestation should be defined as early term.

Udgivelsesdato: 2010-Aug-24 Aim of the study: To estimate if maternal intake of n-3 long-chain polyunsaturated fatty acids (LCPUFA) during pregnancy is related to the risk of epilepsy in the offspring. METHODS: We identified 65,754 live-born singletons from the Danish National Birth Cohort (DNBC, 1996-2002) and followed them for up to 11 years of age. Information on maternal diet in the 4 weeks around the 25th gestational week was obtained from a self-administered food frequency questionnaire and maternal intake of n-3 LCPUFA was estimated from the reported amount and type of fish in diet. Information on epilepsy was obtained from the Danish National Hospital Register. Cox regression models were used to estimate the incidence rate ratios (IRR) of epilepsy. RESULTS: Children born to mothers in the lowest (IRR=1.28, 95% CI: 0.98, 1.67) and highest (IRR=1.33, 95% CI: 1.02, 1.74) quintile of n-3 LCPUFA intake had an increased risk of epilepsy after adjustment for potential confounders compared to children born to mothers with an average intake. The associations may be related to the age of onset of epilepsy. CONCLUSIONS: Maternal deficiency of n-3 LCPUFA and a high intake of n-3 LCPUFA perhaps related to a high consumption of contaminated fish may be associated with an increased risk of epilepsy in early childhood.

Udgivelsesdato: 2010-Jun-25 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.

We asked whether breastfeeding reduces the risk of epilepsy in childhood.We included 69 750 singletons born between September 1997 and June 2003 in the Danish National Birth Cohort and observed them to August 2008. Information on breastfeeding was reported by mothers in two computer-assisted telephone interviews at 6 and 18 months after birth. Information on epilepsy (inpatients and outpatients) was retrieved from the Danish National Hospital Register. Cox proportional hazards regression models were used to estimate incidence rate ratios and 95% CIs.Breastfeeding was associated with a decreased risk of epilepsy, with a dose-response like pattern. For example, children breastfed for 3 to 5, 6 to 8, 9 to 12, and ≥ 13 months had a 26%, 39%, 50%, and 59% lower risk of epilepsy after the first year of life, respectively, compared with children who were breastfed for1 month. The association remained when we excluded children who had adverse neonatal conditions or children who were exposed to adverse maternal conditions during pregnancy.The observed protective effect of breastfeeding may be causal. Breastfeeding may decrease epilepsy in childhood, thereby adding another reason for breastfeeding.

Although a few previous studies have reported an increased risk of epilepsy among children of women with eclampsia, it is unclear whether there is increased risk for children of women with preclampsia. This population-based cohort study evaluated the association between preeclampsia and eclampsia and the risk of epilepsy in all singletons born in Denmark between 1978 and 2004 (n = 1,537,860). Information on mild preeclampsia and severe preeclampsia, unspecified preeclampsia, eclampsia, and epilepsy was acquired from the Danish National Hospital Register. The Danish Medical Birth Registry provided information on gender of the child, gestational age, birthweight, parity, maternal age at birth, and Apgar score at 5 minutes after birth. Cox proportional hazard models were used to estimate the incidence rate ratio (IRR) for associations between preeclampsia (mild, severe, and unspecified) and the risk for epilepsy. IRRs for the associations were estimated according to onset age of epilepsy and the gestational week at birth (20-32, 33-36, 37-41, ≥42 gestational weeks). Among the 1,537,860 singletons, 45,288 (2.9%) were prenatally exposed to preeclampsia (34,823 to mild, 7,043 to severe, and 3,422 to unspecified) and 654 (0.04%) to eclampsia. During up to 27 years of follow-up, 20,260 people with epilepsy were identified. A higher risk of epilepsy was found among children exposed to preeclampsia and eclampsia whose gestational age at birth was at least 37 weeks. Eclampsia was associated with epilepsy with an IRR of 5.03 for children born postterm and 1.29 for children born at term. For severe preeclampsia, the IRRs were 2.57 among children born postterm and 1.41 among children born at term. The IRRs for mild preeclampsia were 1.68 for children born postterm and 1.16 among children born at term. Adjustment for potential confounders decreased the IRR estimates, but mild preeclampsia remained an independent risk factor; the IRR was 1.20 with a 95% confidence interval (CI) of 1.10-1.32). No associations were found between preeclampsia and epilepsy among children born before 37 weeks' gestation. These data show that prenatal exposure to both preeclampsia and eclampsia is associated with an increased risk for epilepsy, but only among children born after 37 weeks of gestation.

Udgivelsesdato: 2009-Feb-1 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.

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.

The authors evaluated the association between gestational age, birth weight, intrauterine growth and epilepsy in a population-based cohort of 1.4 million singletons born in Denmark (1979-2002). A total of 14,334 individuals were registered with epilepsy in the Danish National Hospital Register as inpatients (1979-2002) and outpatients (1995-2002). Information on gestational age and birth weight was obtained from Danish Medical Birth Registry. Children small at birth were identified through two methods: 1) sex-, birth order-, and gestational-age-specific z-score, and 2) deviation from the expected birth weight estimated based on the birth weight of an older sibling. The incidence rates of epilepsy increased consistently with decreasing gestational age and birth weight. The incidence rate ratios (IRR) for epilepsy in the first year of life were more than five-fold in children born at 22-32 weeks compared with children born at 39-41 weeks, and in children with a birth weight

Background Low birth weight is associated with an increased risk of neonatal and infant mortality and morbidity, as well as with other adverse conditions later in life. Since the birth weight-specific mortality of a second child depends on the birth weight of an older sibling, a failure to achieve the biologically intended size appears to increase the risk of adverse outcome even in babies who are not classified as small for gestation. In this study, we aimed at quantifying the risk of neonatal death as a function of a baby's failure to fulfil its biologic growth potential across the whole distribution of birth weight. Methods We predicted the birth weight of 411,957 second babies born in Denmark (1979–2002), given the birth weight of the first, and examined how the ratio of achieved birth weight to predicted birth weight performed in predicting neonatal mortality. Results For any achieved birth weight category, the risk of neonatal death increased with decreasing birth weight ratio. However, the risk of neonatal death increased with decreasing birth weight, even among babies who achieved their predicted birth weight. Conclusion While a low achieved birth weight was a stronger predictor of mortality, a failure to achieve the predicted birth weight was associated with increased mortality at virtually all birth weights. Use of family data may allow identification of children at risk of adverse health outcomes, especially among babies with apparently "normal" growth.

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.

Background To evaluate the impact of surgically induced first-trimester abortion on the risk of miscarriage in a subsequent pregnancy.Methods The study is a pregnancy cohort study. It was conducted among 15 general hospitals or maternity and infant health institutes in Shanghai, China from November 1993 to March 1998. The abortion cohort consisted of pregnant women whose previous pregnancies were terminated by vacuum aspiration (98%). The reference cohort consisted of primigravidae. Subjects were recruited at 35–63 days of gestational age. A total of 2953 pregnant women were enrolled; 1502 in the abortion cohort, 1451 in the reference cohort.Results There were only 62 women lost to follow-up. The remaining 2891 women had 2732 live births, and 137 miscarriages. About 5.5% of pregnancies in the abortion cohort were miscarried and 4.0% in the reference cohort. Once potential confounders were controlled for by logistic regression, odds ratio (OR) of miscarriage between the abortion cohort and the reference cohort was 1.55 (95% CI: 1.08–2.23). The adjusted OR were 2.44 (95% CI: 1.16–5.15) among women who were recruited within 49 days of gestational age, and 1.72 (95% CI: 1.09–2.72) for the first-trimester miscarriage.Conclusions Induced abortion by vacuum aspiration is associated with an increased risk of first-trimester miscarriage in the subsequent pregnancy.

Background: New evidence suggests that advanced paternal age is a reproductive hazard, but we do not know whether paternal age affects the physical conditions of newborn infants as measured by the Apgar score. Methods: We conducted a register-based cohort study of 70,347 couples and their first singleton infants by using data from the Danish Fertility Database (1980–1996). Information on Apgar score was obtained by linking the children to the National Birth Register. Results: The odds ratio for having a baby with a 1-minute Apgar score of 1–3 was 1.64 (95% confidence interval = 1.08–2.48) for fathers 45 to 49 years of age and 1.49 (0.76–2.94) for fathers 50+ years compared with fathers 20 to 29 years (P for trend = 0.011). The risk of having a 5-minute Apgar score less than 7 increased among fathers 45+ years old (P for trend = 0.178). Conclusions: Our data suggest a modest effect of advanced paternal age on the Apgar score.

Purpose The aim of the study was to estimate the association between newborn children treated with phototerapy for hyperbilirubinemia and the subsequent risk of febrile seizures or epilepsy in early childhood. Methods We conducted a follow-up study of singleton children (N = 70 230) born between February 1998 and May 2003 from the Danish National Birth Cohort (DNBC). Information on exposure to phototherapy for hyperbilirubinemia was obtained from a questionnaire in the DNBC. Information on epilepsy and febrile seizures were obtained from the Danish National Hospital Registry (DNHR). Cox proportional hazard regression model was used to calculate hazard ratios (HRs) with 95% confidence intervals (CI). Results Newborns treated with phototherapy for hyperbilirubinemia had a higher risk of developing epilepsy in early childhood (HR: 1.66, 95% CI: 1.23–2.24) but not febrile seizures (HR: 1.04, 95% CI: 0.86–1.27). The increases risk of epilepsy were only present for boys (HR: 1.98, 95% CI: 1.40–2.78) not for girls (HR: 1.14, 95% CI: 0.64–2.02) Conclusion Phototherapy for hyperbilirubinemia in newborns was associated with an increased risk of epilepsy for males in early childhood. No excess risk was seen with febrile seizures.