Prenatal opioid exposure and risk of asthma in childhood: a population-based study from Denmark, Norway, and Sweden

Background: Opioids may modulate the immune function through opioid receptors on immune cells. Long-term consequences of prenatal opioid exposure on the immune system, such as childhood asthma, are unknown.Objectives: To investigate whether prenatal opioid exposure is associated with the risk of childhood asthma.Methods: Cohort study using linked nationwide registers in Denmark (1996–2015), Norway (2005–2015), and Sweden (2006–2013). Children born by mothers who were chronic opioid analgesics users before pregnancy (n = 14,764) or who were receiving opioid maintenance therapy (OMT) before or during pregnancy (n = 1,595) were identified based on information from each of the medical birth registers and prescription registers. Long-term opioid analgesics exposed children were compared to short-term exposed or unexposed, whereas OMT exposed children were compared to OMT unexposed. Asthma among children ≥1 years of age was defined as two or more filled prescriptions of antiasthmatic medication within 365 days, or a diagnosis of asthma. Hazard ratios (HRs) were calculated using Cox proportional hazards regression with attained age as the time scale. Inverse probability of treatment weights based on propensity scores were applied to adjust for measured confounders. Individual level data from Norway and Sweden were pooled, whereas individual level data from Denmark were analyzed separately. For the opioid analgesics comparisons, adjusted HRs (aHR) from the combined Norwegian/Swedish data and the Danish data were pooled in a fixed-effects meta-analysis.Results: For the opioid analgesics cohort, no increased risk of asthma was observed in long-term exposed children neither compared with unexposed [aHR = 0.99 (95% CI 0.87-1.12)], nor compared with short-term exposed [aHR = 0.97 (0.86-1.10)]. No increased risk of asthma was observed in OMT exposed compared with OMT unexposed children [Norway/Sweden: aHR = 1.07 (0.60-1.92), Denmark: aHR = 1.25 (0.87-1.81)]. Results from sensitivity analyses, where potential misclassification of the outcome and misclassification of OMT exposure were assessed, as well as starting follow-up at 6 years of age, showed that the estimates of association were generally robust.Conclusion: We found no association between prenatal exposure to opioids and risk of childhood asthma. Results were consistent across two different opioid exposure groups with different confounder distributions

Characterization of new chemical compounds acting as cyclic AMP signalling enhancers or disruptors in human peripheral T cells and monocytes

Abstract Opportunistic infections due to impaired function of T cells are the main cause of death in HIV infected individuals. It has been shown that T cells from these individuals have elevated levels of cAMP, which inhibits proliferation of T cells through interaction with PKA type I (Skålhegg et al. 1994, Hofmann et al. 1993). Presence of the HIV virus induces cAMP, and cAMP will in turn enhance viral replication (Nokta et al. 1992). By blocking this hyperactivated cAMP/PKA inhibitory pathway, it is possible to normalize proliferation of T cells, and reverse dysfunction caused by the infection. Rp-8-Br-cAMPS, a specific PKA type I antagonist was shown to reverse the inhibition of proliferation of T cells from HIV infected individuals (Aandahl et al. 1998). These findings have given rise to the current drug development project that is trying to find a suitable drug candidate with lowered therapeutic concentration in vivo and higher degree of specificity towards PKA type I than the lead compound Rp-8-Br-cAMPS. Results reported in the first part of this thesis shows that none of analogs tested had a potency higher than Rp-8-Br-cAMPS and that none of them appeared to have toxic properties. O`benzyl ester of Sp-8-Br-cAMPS was toxic at concentrations higher than 125 M, and was not able to inhibit proliferation of T cells to a similar degree as PKA type I agonist Sp-8-Br-cAMPS. Monocytes express Epac1, that is activated by treatment with 8-CPT-2-O`-Me-cAMP and 8-Br-2-O`-Me-cAMP-AM. Epac1 further activates Rap1 leading to a set of biological responses yet to be determined. Sp-8-Br-cAMPS, a specific PKA type I agonist also activates Epac1 but this activation is strongly impaired when compared with Epac1 specific agonists. Involvement of the PKA shown by induction of phosphorylation after treatment with Sp-8-Br-cAMPS and 8-Br-2-O`-Me-cAMP-AM opens for a possibility for interference between PKA and Epac1 pathway in monocytes. In the second part of these master thesis the effects of activation of Rap1 and PKA on production of cytokines in monocytes are studied

Epidemiological and Serological Investigation into the Role of Gestational Maternal Influenza Virus Infection and Autism Spectrum Disorders

The literature concerning gestational maternal influenza virus infection and risk of autism spectrum disorders (ASD) is inconclusive. To address this uncertainty, we obtained information from questionnaires and samples from the Autism Birth Cohort, a prospective birth cohort comprising mothers, fathers, and offspring recruited in Norway in 1999 to 2008. Through questionnaires, referrals, and linkages to the Norwegian National Patient Registry, we identified 338 mothers of children with ASD and 348 frequency-matched controls for whom plasma samples that had been collected midpregnancy and after delivery were available for influenza virus serology via luciferase immunoprecipitation and hemagglutinin inhibition assays for influenza virus strains circulating during the study period. Assay data were combined to define serological status and integrated with self-reports of influenza-like illness to estimate ASD risk. Neither influenza A nor influenza B virus infection was associated with increased ASD risk. Integration of reports of symptoms of influenza-like illness with serology revealed an increase in risk for seropositive women with symptoms, but this increase did not achieve statistical significance (a level of P < 0.05) in the comparison with seronegative women without symptoms (adjusted odds ratio, 1.93; 95% confidence interval, 0.95 to 3.89; P = 0.068). Although chance may explain our findings, the magnitude of the potential association may be of biological importance, and dismissing our findings could result in failure to detect a bona fide association (type II error). If the association is true, we posit that the risk is due to activation of the maternal immune system following infection rather than direct fetal infection. Data on levels of cytokines or other mediators of inflammation would allow us to test the validity of this hypothesis

Prevalence of use of non-prescription analgesics in the Norwegian HUNT3 population: Impact of gender, age, exercise and prescription of opioids

Background There are concerns about potential increasing use of over-the-counter (OTC) analgesics. The aims of this study were to examine 1) the prevalence of self-reported use of OTC analgesics; 2) the prevalence of combining prescription analgesics drugs with OTC analgesics and 3) whether lifestyle factors such as physical activity were associated with prevalence of daily OTC analgesic use. Methods Questionnaire data from the Nord–Trøndelag health study (HUNT3, 2006–08), which includes data from 40,000 adult respondents. The questionnaire included questions on use of OTC analgesics, socioeconomic conditions, health related behaviour, symptoms and diseases. Data were linked to individual data from the Norwegian Prescription Database. A logistic regression was used to investigate the association between different factors and daily use of paracetamol and/or non-steroid anti-inflammatory drugs (NSAIDs) in patients with and without chronic pain. Results The prevalence of using OTC analgesics at least once per week in the last month was 47%. Prevalence of paracetamol use was almost 40%, compared to 19% and 8% for NSAIDs and acetylsalicylic acid (ASA), respectively. While the use of NSAIDs decreased and the use of ASA increased with age, paracetamol consumption was unaffected by age. Overall more women used OTC analgesics. About 3-5% of subjects using OTC analgesics appeared to combine these with the same analgesic on prescription. Among subjects reporting chronic pain the prevalence of OTC analgesic use was almost twice as high as among subjects without chronic pain. Subjects with little physical activity had 1.5-4 times greater risk of daily use of OTC compared to physically active subjects. Conclusions Use of OTC analgesics is prevalent, related to chronic pain, female gender and physical inactivity

An 11-year nationwide registry-linkage study of opioid maintenance treatment in pregnancy in norway

Aim: We aimed to describe opioid maintenance treatment (OMT) to pregnant women in Norway and study thebackground characteristics of the pregnant women compared to the general population of pregnant women andto a previous clinical cohort study of OMT in pregnancy.Methods: Population-based cohort study with linked data from the Norwegian Medical Birth Registry, theNorwegian Prescription Database, the Norwegian Patient Registry, and Statistics Norway. The study populationconsisted of women giving birth between 2005-2015 in Norway. We defined OMT pregnancies as pregnancieswhere the woman was dispensed OMT medications (methadone, buprenorphine, or buprenorphine/naloxone) at least once during pregnancy.Results: The study population consisted of 420,808 women with 645,440 pregnancies ending in a live birth inNorway in 2005-2015 (the general pregnant population). Of these, 261 women (0.6‰) had altogether 306OMT pregnancies. The mean number of pregnancies was 28 OMT pregnancies per year and quite stable duringthe study period. Women with OMT pregnancies were older, smoked tobacco more frequently, had lowereducation, and fewer of them had a partner, compared to the general population of pregnant women. In mostpregnancies, the women were treated with buprenorphine (n=183 (59.8%)), while in 120 (39.2%) pregnancies,the woman received methadone. From 2008, buprenorphine replaced methadone as the most frequently useddrug. In only 38 (12.4%) pregnancies, OMT treatment was initiated in pregnancy. In 201 (66%) pregnancies,the woman used OMT medications in all trimesters. For these women, the mean amount of dispensed drug was3.4 DDD/day (85 mg/day) in pregnancy for methadone and 1.9 DDD/day (15.2 mg/day) for buprenorphine.Conclusion: The number of OMT pregnancies per year has been low and stable in the period 2005-2015.Following Norwegian recommendations, there has been a shift from treatment with methadone towardsbuprenorphine. The women receiving OMT during pregnancy had more risk factors for adverse outcomes thanthe general pregnant population but were quite similar to the previous clinical cohort

Prenatal methamphetamine exposure and adverse neonatal outcomes: A nationwide cohort study

Background: There is limited knowledge on the adverse outcomes in newborns after maternal methamphetamine (MA) use during pregnancy. Objectives: To compare neonatal outcomes in newborns exposed to MA with the newborns of opioid-exposed mothers and of mothers from the general population (GP). Method: A cohort study using nationwide registries in Czechia (2000–2014). Women hospitalized with a main diagnosis of MA use disorder during pregnancy (n = 258) and their newborns were defined as MA-exposed. The comparison groups consisted of women (n = 199) diagnosed with opioid use disorder during pregnancy, defined as opioid-exposed, and women (n = 1,511,310) with no substance use disorder diagnosis (GP). The neonatal outcomes studied were growth parameters, gestational age, preterm birth, and Apgar score. To explore the associations between MA exposure and neonatal outcomes, regression coefficients (b) and odds ratios from multivariable linear and binary logistic regression were estimated. Results: MA-exposed women had similar socio-economic characteristics to opioid-exposed, both of which were worse than in the GP. After adjustment, MA exposure was associated with a more favourable birthweight when compared to the opioid-exposed (adjusted mean differences [aMD] b = 122.3 g, 95% CI: 26.0–218.5) and length (aMD b = 0.6 cm, 0.0–1.1). Unadjusted results from the comparison with the GP showed that the MA group had poorer neonatal outcomes, especially in the growth parameters. Adjustment for background characteristics had a profound effect on the comparison with the GP. After adjustment, MA exposure was associated only with a slightly reduced birthweight (aMD b = −63.0 g, −123.0 to −3.1) and birth length (aMD b = −0.3 cm, −0.6 to 0.0). Conclusions: Although the observed negative outcomes were large in the MA-exposed newborns, the adjustment had a profound effect on the comparison with the GP, indicating the large influence of lifestyle and socio-economic factors in these high-risk pregnancies. MA-exposed newborns had better neonatal outcomes compared to opioids-exposed

Prenatal methamphetamine exposure and adverse neonatal outcomes: A nationwide cohort study

Background: There is limited knowledge on the adverse outcomes in newborns after maternal methamphetamine (MA) use during pregnancy. Objectives: To compare neonatal outcomes in newborns exposed to MA with the newborns of opioid-exposed mothers and of mothers from the general population (GP). Method: A cohort study using nationwide registries in Czechia (2000–2014). Women hospitalized with a main diagnosis of MA use disorder during pregnancy (n = 258) and their newborns were defined as MA-exposed. The comparison groups consisted of women (n = 199) diagnosed with opioid use disorder during pregnancy, defined as opioid-exposed, and women (n = 1,511,310) with no substance use disorder diagnosis (GP). The neonatal outcomes studied were growth parameters, gestational age, preterm birth, and Apgar score. To explore the associations between MA exposure and neonatal outcomes, regression coefficients (b) and odds ratios from multivariable linear and binary logistic regression were estimated. Results: MA-exposed women had similar socio-economic characteristics to opioid-exposed, both of which were worse than in the GP. After adjustment, MA exposure was associated with a more favourable birthweight when compared to the opioid-exposed (adjusted mean differences [aMD] b = 122.3 g, 95% CI: 26.0–218.5) and length (aMD b = 0.6 cm, 0.0–1.1). Unadjusted results from the comparison with the GP showed that the MA group had poorer neonatal outcomes, especially in the growth parameters. Adjustment for background characteristics had a profound effect on the comparison with the GP. After adjustment, MA exposure was associated only with a slightly reduced birthweight (aMD b = −63.0 g, −123.0 to −3.1) and birth length (aMD b = −0.3 cm, −0.6 to 0.0). Conclusions: Although the observed negative outcomes were large in the MA-exposed newborns, the adjustment had a profound effect on the comparison with the GP, indicating the large influence of lifestyle and socio-economic factors in these high-risk pregnancies. MA-exposed newborns had better neonatal outcomes compared to opioids-exposed