Maternal use of hormonal contraception and epilepsy in offspring.

STUDY QUESTION: Is maternal use of hormonal contraception associated with the development of epilepsy in the offspring? SUMMARY ANSWER: We found that maternal use of hormonal contraception was associated with a slightly increased risk of epilepsy in the offspring. WHAT IS KNOWN ALREADY: Foetal exposure to exogenous hormones has been associated with changes in brain development. However, little is known about maternal hormonal contraception use and development of epilepsy in the offspring. STUDY DESIGN, SIZE, DURATION: A nationwide cohort of all live born children born in Denmark between 1 January 1998 and 31 December 2014, was followed from day 29 after birth for epilepsy (first diagnosis of epilepsy or first redeemed prescription for anti-epileptic medication) to censoring (emigration, death) or 31 December 2015, whichever occurred first. PARTICIPANTS/MATERIALS, SETTING, METHODS: Diagnoses of epilepsy were obtained from the National Patient Registry. The Danish National Prescription Registry supplied information on redeemed prescriptions for hormonal contraception and anti-epileptic medication. Maternal hormonal contraception use was categorized as never use (reference group), previous use (prescriptions redeemed >3 months before pregnancy start) and recent use (prescriptions redeemed ≤3 months before or during pregnancy). MAIN RESULTS AND THE ROLE OF CHANCE: The data show that 17 585 children developed epilepsy during a median follow-up of 9.2 years (9 732 635 person-years). The hazard ratio (HR) for epilepsy was 1.07 (95% CI 1.02-1.13) in children of mothers who had used any type of hormonal contraception recently, compared with children of mothers who had not used hormonal contraception. The HR was similar for recent use of oral combined products, while the HRs for recent or previous use of non-oral combined products were 1.32 (95% CI 0.98-1.77) and 1.16 (95% CI 1.02-1.32), respectively. For non-oral progestin-only products, the HRs were 1.19 (95% CI 1.04-1.38) and 1.53 (95% CI 1.31-1.80), respectively, for recent and previous use. LIMITATIONS, REASONS FOR CAUTION: There may be some misclassification of maternal hormonal contraception use, as some women may not have used the redeemed prescriptions or used them at a different point in time; potentially leading to an attenuation of the estimates. In addition, although we were able to account for known risk factors for epilepsy, unknown or residual confounding cannot be ruled out. WIDER IMPLICATIONS OF THE FINDINGS: Our findings are based on nationwide population-based data and can therefore be applied to other similar populations. However, as this is the first study in this field, further studies are needed to confirm our findings. STUDY FUNDING/COMPETING INTEREST(S): No specific funding was obtained for this study, which was supported by internal funding at the Unit of Virus, Lifestyle and Genes. All authors report no conflicts of interest. TRIAL REGISTRATION NUMBER: N/A.

Perinatal outcomes following an earlier post-term labour induction policy: a historical cohort study.

OBJECTIVE: To assess the changes in perinatal outcomes in children born from 37 weeks of gestation after implementation of a more proactive labour induction practice from 2009. DESIGN: Register-based cohort study. SETTING: Denmark, 2000-12. POPULATION: Newborns from 37 weeks of gestation. METHODS: Perinatal outcomes were estimated using a logistic regression analysis with adjustment for gestational age, maternal age, parity, plurality, smoking and body mass index. MAIN OUTCOME MEASURES: Perinatal outcomes. RESULTS: A total of 770 926 infants were included. Labour induction from 37 weeks increased from 9.7% in 2000-02 to 22.5% in 2011-12. From 2003-05 to 2011-12, the risk of umbilical cord pH < 7.0 decreased by 23%; odds ratio (OR) 0.77 (95% confidence interval 0.67-0.89), and the adjusted OR of Apgar score < 7 at 5 minutes was unchanged. The risk of admission to neonatal intensive care units increased by 56%; OR 1.56 (1.47-1.66), whereas the risk of neonatal deaths decreased by 44%; OR 0.56 (0.45-0.70). The risk of cerebral palsy was from 2000-02 to 2009-10 reduced by 26%; OR 0.74 (0.60-0.90). The proportion of infants born with fetal weight ≥ 4500 g decreased by one-third; OR 0.68 (0.65-0.71). However, the risk of shoulder dystocia increased by 32%; OR 1.32 (1.21-1.44), whereas the risk of peripheral nerve injuries was reduced by 43%; OR 0.57 (0.45-0.73). CONCLUSION: The results suggest an overall improvement in perinatal outcomes as a result of a more proactive post-term labour induction practice.

Association of obesity and insulin resistance with asthma and aeroallergen sensitization.

BACKGROUND: It has been hypothesized that obesity and insulin resistance may play a role in the development of asthma and allergy. The aim of the study was to examine the association of obesity and insulin resistance with asthma and aeroallergen sensitization. METHODS: Cross-sectional population-based study of 3609 Danish men and women aged 30-60 years. Aeroallergen sensitization was defined as positive levels of specific IgE against a panel of inhalant allergens. Asthma was defined as self-reported physician diagnosed asthma. Allergic asthma was defined as the presence of both asthma and aeroallergen sensitization. The homeostasis model assessment of insulin resistance was used to estimate the degree of insulin resistance. Body mass index, waist-to-hip ratio, and waist circumference were used as measures of obesity. Data were analyzed by multiple logistic regression analyses. RESULTS: Obesity was associated with increased risk of aeroallergen sensitization as well as allergic and nonallergic asthma. Insulin resistance was asssociated with aeroallergen sensitization and allergic asthma, but not nonallergic asthma. The associations of obesity with aeroallegen sensitization and allergic asthma became nonsignificant after adjustment for insulin resistance, whereas the association of obesity with nonallergic asthma was unaffected. No sex-differences were observed. CONCLUSION: Obesity may be related to an increased risk of aeroallergen sensitization and allergic asthma through mechanisms also involved in the development of insulin resistance.

Drinking pattern and mortality in Danish nurses.

BACKGROUND/OBJECTIVE: Moderate alcohol consumption has beneficial effects on survival. Sex differences, however, have been suggested implying less beneficial effect among women. We examined the impact of alcohol consumed on weekdays and at weekends, respectively, on risk of death among women. SUBJECTS AND METHODS: At baseline in 1993, a total of 17 772 female members of the Danish Nurse Association completed questionnaires on alcohol intake and other lifestyle factors. The influence of alcohol intake on risk of death was analyzed using Cox proportional hazard model. RESULTS: Alcohol intake of 1-3 drinks per week was associated with the lowest risk of death. Intake above six drinks per weekend (Friday through Sunday) increased risk of death from all causes by 3% for each additional drink consumed per weekend (corresponding to an increased risk by 9% per drink per weekend day). Consumption of one or more drinks per weekday (Monday, Tuesday, Wednesday or Thursday) increased risk by 4% for each additional drink consumed per day. CONCLUSIONS: The results indicated an increasing risk of death for intake above six drinks per weekend and of one or more drinks per weekday.

Interleukin-1 beta (IL-1) does not reduce the diabetes incidence in diabetes-prone BB rats.

The cytokine interleukin 1 beta (IL-1) has been implicated as a pathogenetic factor in the initial events leading to insulin-dependent diabetes mellitus. Previous studies investigating the impact of IL-1 on diabetes incidence in spontaneously diabetic rodent models have been conflicting. IL-1 induces anorexia and previous studies are hampered by the lack of pair-fed controls to the IL-1 treated animals. We report that daily injections of 4.0 micrograms/kg/day of recombinant human IL-1 (rhIL-1) for 13 weeks from 25-30 days of age did not alter the incidence of diabetes in the diabetes-prone (DP) BB rats (75%) when compared to pair-fed, vehicle treated controls (55%, p = 0.18), or to unhandled DP BB rats (80%, p = 0.71). However, IL-1 induced significantly higher blood glucose concentrations in the prediabetic period (p < 0.00005) and at diabetes onset (p < 0.00005) in the DP BB rats and caused episodes of blood glucose concentrations > 11 mmol/l in the prediabetic period in 11/20 DP BB rats compared to 4/27 diabetes-resistant (DR) BB rats and 4/28 Wistar Furth (WF) rats (both p < 0.004), compared to DP BB). Further, rhIL-1 induced fever in 11 weeks in the DP BB rats compared to 3 weeks in the DR BB and 6 weeks in the WF rats. Using high performance size exclusion chromatography specific anti-rhIL-1-antibodies were demonstrated in DR BB and WF, but not in DP BB rats. These antibodies neutralized the inhibitory effect of rhIL-1 on insulin secretion from isolated islets of Langerhans in vitro. The reduced pyrogenic and endocrine effect of rhIL-1 in the DR BB and WF rats compared to the DP BB rats could be explained by the impaired ability of the DP BB rats to produce anti-rhIL-1-antibodies. In conclusion, administration of rhIL-1 modulated the prediabetic period, and produced higher blood glucose concentrations at diagnosis, but did not change the diabetes incidence in DP BB rats. The results are not in conflict with the hypothesis that IL-1 is a pathogenetic factor in IDDM, caused by high local concentrations of rat IL-1 in the islets during early insulitis. The results also show the necessity of pair-feeding of the control group to the rhIL-1 group when interpreting data from experiments investigating rhIL-1 effects on diabetes development in animal models.

Differential interleukin-1 receptor antagonism on pancreatic beta and alpha cells. Studies in rodent and human islets and in normal rats.

The monokines interleukin-1 alpha and -beta have been implicated as effector molecules in the immune-mediated pancreatic beta-cell destruction leading to insulin-dependent diabetes mellitus. Here we investigated the effects of interleukin-1 receptor antagonism on insulin and glucagon release of rat, mouse and human islets exposed to recombinant human interleukin-1 beta, and on interleukin-1 beta induced changes in blood glucose, serum insulin and serum glucagon levels in Wistar Kyoto rats. The interleukin-1 receptor antagonist reduced the co-mitogenic effect of interleukin-1 beta on mouse and rat thymocytes with a 50% inhibitory concentration of 10- and 100-fold molar excess, respectively. Complete inhibition was obtained with a 100-1,000-fold molar excess. However, at a 100-fold molar excess the interleukin-1 receptor antagonist did not antagonise the potentiating effect of interleukin-1 beta on rat islet insulin accumulation during 3 and 6 h of exposure or of interleukin-1 beta-induced inhibition of insulin release after 24 h. In contrast, interleukin-1 beta-stimulated islet glucagon release was completely antagonised by a 100-fold molar excess of interleukin-1 receptor antagonist. A 10,000-fold molar excess of interleukin-1 receptor antagonist was needed to antagonise interleukin-1 beta stimulatory and inhibitory effects on rat beta-cell function in vitro. A 100-fold excess of interleukin-1 receptor antagonist could not counteract interleukin-1 beta effects on mouse and human beta cells, excluding species difference in the efficacy of the human interleukin-1 receptor antagonist.(ABSTRACT TRUNCATED AT 250 WORDS)

Involvement of interleukin 1 and interleukin 1 antagonist in pancreatic beta-cell destruction in insulin-dependent diabetes mellitus.

In this review we propose that the balance between the action of interleukin 1 (IL-1) and its natural antagonist IL-1ra on the level of the insulin-producing pancreatic beta-cell may play a decisive role in the pathogenesis of insulin-dependent diabetes mellitus (IDDM). We argue that IL-1 potentiated by other cytokines (tumor necrosis factor alpha, interferon gamma) is an important effector molecule involved in both early and late events in the immune-mediated process that leads to beta-cell destruction and IDDM. We also point out that surprisingly high molar excesses of IL-1ra over IL-1 are necessary to block the action of IL-1 on islet beta-cells compared to islet alpha-cells in vitro and in animals. We suggest that the selectivity of beta-cell destruction in IDDM may be conferred on several levels: (1) homing of beta-cell antigen specific T cells, (2) targeted delivery of cytokines by lymphocytic and monocytic cells beta-cells, (3) high molar excesses of IL-1ra over IL-1 needed to prevent IL-1 mediated beta-cell toxicity, (4) increased beta-cell sensitivity to free nitric oxide and oxygen radical formation induced by IL-1 and (5) inadequate oxidative stress response by beta-cells to cytokines. Further studies are needed to establish the in vivo role of an imbalance between the amounts of IL-1 and IL-1ra produced relative to their action in the pathogenesis of IDDM.

Characterisation of the citrate synthase reaction with propionyl-CoA.

Experiments with propionyl-CoA stereoselectively deuteriated in the propionyl moiety demonstrate that the formation of (2S,3S)-methylcitric acid (1) catalysed by citrate (si)-synthase occurs with inversion of configuration in the propionyl moiety; the absolute configurations of the methylcitric acids 1 and 2 indicate a si attack on oxaloacetate. Deuterium in the pro-S position is exchanged for protium 60 times faster than deuterium in the pro-R position. Experiments with (R,S)-(2-2H1)propionyl-CoA allowed the determination of isotope effects. For the enzymatic formation of 1, a primary deuterium isotope effect kH/kD = 1.8 and a secondary alpha-deuterium isotope effect kH/kD = 0.99 were calculated; both are effects on Vmax/KM.

Isotope dilution analysis of methylcitric acid in amniotic fluid for the prenatal diagnosis of propionic and methylmalonic acidemia.

A stable isotope dilution assay for methylcitric acid in amniotic fluid was developed to provide rapid prenatal diagnosis of the inherited disorders propionic acidemia and methylmalonic acidemia. The method utilizes two 2H3-labeled diastereoisomers of methylcitric acid as internal standards, isolation by liquid partition chromatography and quantitation of the trimethyl esters by chemical ionization selected ion monitoring gas chromatography-mass spectrometry. Methylcitric acid at a concentration of 0.38 +/- 0.10 mumol/l was detected in normal amniotic fluid. Highly elevated levels of 7.87 and 9.16 mumol were found in the fluids surrounding fetuses affected with propionic acidemia and levels of 1.79, 2.72 and 12.27 mumol were found for fetuses with methylmalonic acidemia. Methylcitric acid was not elevated in the amniotic fluid of a fetus heterozygous for propionic acidemia. In the five pregnancies at risk for propionic acidemia, and three pregnancies at risk for methylmalonic acidemia, the levels of methylcitric acid in amniotic fluid gave the diagnosis in all cases. Measurement of methylcitric acid in amniotic fluid therefore provides a rapid and reliable method for the prenatal diagnosis of these genetic disorders.