Search

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.

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.

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.

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.

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.

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.