Marte Handal

Cohort Profile Update: The Norwegian Mother and Child Cohort Study (MoBa)

This is an update of the Norwegian Mother and Child Cohort Study (MoBa) cohort profile which was published in 2006. Pregnant women attending a routine ultrasound examination were initially invited. The first child was born in October 1999 and the last in July 2009. The participation rate was 41%. The cohort includes more than 114 000 children, 95 000 mothers and 75 000 fathers. About 1900 pairs of twins have been born. There are approximately 16 400 women who participate with more than one pregnancy. Blood samples were obtained from both parents during pregnancy and from mothers and children (umbilical cord) after birth. Samples of DNA, RNA, whole blood, plasma and urine are stored in a biobank. During pregnancy, the mother responded to three questionnaires and the father to one. After birth, questionnaires were sent out when the child was 6 months, 18 months and 3 years old. Several sub-projects have selected participants for in-depth clinical assessment and exposure measures. The purpose of this update is to explain and describe new additions to the data collection, including questionnaires at 5, 7, 8 and 13 years as well as linkages to health registries, and to point to some findings and new areas of research. Further information can be found at [www.fhi.no/moba-en]. Researchers interested in collaboration and access to the data can complete an electronic application available on the MoBa website above.

Pharmacokinetic differences of morphine and morphine-glucuronides are reflected in locomotor activity

The main metabolites of morphine, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G), have been considered to participate in some of the effects of morphine. There is limited knowledge of the pharmacokinetics and dynamics of morphine and the main metabolites in mice, but mice are widely used to study both the analgesic effects and the psychomotor effects of morphine. The present study aimed to explore pharmacokinetic differences between morphine and morphine-glucuronides in mice after different routes of administration, and to investigate how possible differences were reflected in locomotor activity, a measure of psychostimulant properties. Mice were given morphine, M3G or M6G by different routes of administration. Serum concentrations versus time curves, pharmacokinetic parameters and locomotor activity were determined. Intraperitoneal administration of morphine reduced the bioavailability compared to intravenous and subcutaneous administration, but not so for morphine-glucuronides. The two morphine-glucuronides had similar pharmacokinetics, but morphine demonstrated higher volume of distribution and clearance than morphine-glucuronides. The present results demonstrated no locomotor effect of M3G, but a serum concentration effect relationship for morphine and M6G. When serum concentrations and effect changes were followed over time, there was some right hand shifts with respect to locomotor activity, especially during the declining phase of the concentration curve and particularly for M6G.

Midlife vascular risk factors and their association with dementia deaths: results from a Norwegian prospective study followed up for 35 years.

There is growing evidence that midlife risk factors for vascular disease also are risk factors for dementia, but there is still need for long-term observational studies to address this. Our objective was to investigate the association of midlife vascular disease risk factors with dementia death. Participants were included in The Norwegian Counties Study (NCS) in the period 1974-78, aged 35-50 years at baseline. Information from NCS was linked with the Cause of Death Registry through the year 2009 using the unique personal identification number. The study included 48,793 participants, 1.5 million person years and 486 dementia deaths (187 Alzheimers; 299 non-Alzheimers dementia). Cox regression for cause-specific hazards was used. Dementia death was associated with increased total cholesterol levels (>7.80 vs. <5.20 mmol/l: HR=2.01, 95% confidence interval 1.37-2.93); diabetes (HR=2.43, 95% CI 1.40-4.32) and low body mass index (<20 kg/m(2) vs. 20-25 kg/m(2): HR=1.76, 95% CI 1.15-2.68) in midlife. The associations remained after adjustment for other vascular risk factors and educational level. Smoking status or blood pressure in midlife was not significantly associated with risk of dementia death, although the results indicate a possible increased risk in heavy smokers. People suffering from high cholesterol levels, diabetes or underweight in midlife are at increased risk of dying from or with dementia later in life. Our findings add to previous results suggesting that intervention in midlife may be important. To better understand the mechanisms involved in the associations between midlife underweight, diabetes, and elevated cholesterol level and late-life dementia death, these links need to be further investigated.

Prenatal exposure to antidepressants and language competence at age three: results from a large population-based pregnancy cohort in Norway

To examine the association between maternal use of selective serotonin reuptake inhibitors (SSRI) in pregnancy and language competence in their children at age three taking into account maternal symptoms of anxiety and depression.

To what extent does a cohort of new users of weak opioids develop persistent or probable problematic opioid use

&NA; When opioid therapy is initiated for a new pain condition, it may be unknown whether the pain will persist beyond the time of tissue healing. The aim of this study was to determine the prevalence of prescription patterns indicating persistent and/or problematic opioid use in a cohort of opioid‐naive patients starting therapy with weak opioids. Data were drawn from the nationwide Norwegian Prescription Database. The study population was all new users of opioids receiving prescriptions of a weak opioid in 2005 for nonmalignant pain. This cohort was followed until December 2008. In order to be classified as having probable problematic opioid use, patients had to meet all of the following criteria: received opioids at least once every year from 2005 to 2008 and in 2008; (1) were dispensed more than 365 defined daily doses (DDDs) of opioids; (2) received opioid prescriptions from more than 3 doctors; and (3) were dispensed more than 100 DDDs of benzodiazepines. There were 245,006 persons who were new users of weak opioids in 2005 (216,902 codeine, 26,326 tramadol, 1778 dextropropoxyphene). There were 17,252 (7% of new users) who received a prescription for opioids at least once each of the 3 following years. Of these subjects, 686 patients were dispensed more than 365 DDDs of opioids in 2008 and are probably persistent users. There were 191 subjects who met our criteria for probable problematic opioid use. In a cohort of new opioid users who started treatment with weak opioids, only 0.3% and 0.08% developed prescription patterns indicating persistent opioid use and problematic opioid use, respectively. A national Norwegian cohort of new users of weak opioids was followed from 2005 until 2009; only 0.08% developed problematic opioid use.

Nicotine Dependence Predicts Repeated Use of Prescribed Opioids. Prospective Population-based Cohort Study

PURPOSE The aim of this study was to evaluate prospectively smoking dependence as a predictor of repeated use of prescribed opioids in non-cancer patients. METHODS We conducted a prospective population-based study cohort of 12,848 men and 15,894 women 30-75 years of age in health surveys in Norway during 2000-2002 with repeated opioid prescriptions (12+, during 2004-2007) recorded in the Norwegian Prescription Database as the outcome measure. Information on history of smoking and potential confounders was obtained at baseline by self-administered questionnaires. For smoking, participants were divided into categories: never; previously heavy (stopped maximum of 5 years earlier; 10+ cigarettes daily); daily not heavy (1-9 cigarettes); dependent daily smokers (10+ cigarettes), and other (previously and/or not daily). Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated by logistic regression. RESULTS During follow-up, 335 (1.5%) of survey participants were registered with 12+ prescriptions of opioids during the period 2004-2007. The prevalence of repeated prescription frequency of opioids was higher for men and women with a history of smoking. The adjusted OR for prescribed opioids for dependent daily smokers was 3.1 (95% CI: 2.3-4.1), for daily non-heavy smokers 1.8 (1.2-2.7), and for previous heavy smokers 1.8 (1.1-3.0), compared with never-smokers as reference. CONCLUSIONS Results of the study suggest that smoking dependence may predict more frequent use of opioids.

Drug exposure: inclusion of dispensed drugs before pregnancy may lead to underestimation of risk associations

OBJECTIVES To assess the impact of exposure misclassification on risk associations when using prescription databases as the source for drug exposure in pregnancy by applying results from a validation analysis of exposure classification. STUDY DESIGN AND SETTING Linkage of data on 27,656 participants in the Norwegian Mother and Child Cohort Study (MoBa) with the Norwegian Prescription Database (NorPD). Exposure to selective serotonin reuptake inhibitors (SSRIs) was defined by dispensed drugs during pregnancy including different time windows before pregnancy. The validity of NorPD data was estimated using self-reported use in MoBa as the reference standard. We applied the results from the validation analysis on data from a Nordic study on SSRI use in pregnancy and risk of persistent pulmonary hypertension in the newborn. RESULTS Sensitivity increased and specificity decreased when the time window in NorPD was expanded before pregnancy. Using the same time window as in the Nordic study (+90 days before pregnancy), for use in early pregnancy, the odds ratio (OR) corrected for misclassification was 2.6 compared with the OR of 1.6 in the Nordic study. CONCLUSION Expansion of the time window to include intervals before pregnancy can lead to lower specificity and underestimation of risk associations.

Hypnotic drug use among 0–17 year olds during 2004–2011: A nationwide prescription database study

Aims: To (a) describe the prevalence, trend, and amount of hypnotic drug use, (b) determine the prevalence of chronic diseases among hypnotic drug users, and (c) determine levels of recurrent hypnotic drug use (2007–2011), among 0–17 year old Norwegians. Methods: Data were obtained from the nationwide Norwegian Prescription Database (NorPD) in the period 2004–2011. Results: Hypnotic drug use in 0–17 year olds increased during the period, from 8.9 to 12.3 per 1000, mainly owing to doubling of melatonin use. Hypnotic drug use peaked at 15 per 1000 among those aged 1–2 years. Melatonin use increased steadily from 6 to 12 years of age, most pronounced in males. Among females, hypnotic drug use increased threefold from 13 to17 years of age. Melatonin was dispensed in the highest annual amount of all hypnotic drugs; accounting up to a median of 360 defined daily doses in 9–13 year old boys. A total of 62% and 52% of all male and female hypnotic drug users were co-medicated with reimbursable drugs for chronic diseases. Levels of recurrent use (2007–2011) were 12% in boys and 8% in girls, of whom 76–77% were co-medicated with drugs reimbursed for chronic diseases. Conclusions: There is a trend of increasing use of hypnotic drugs among 0–17 year olds, mainly owing to increasing use of melatonin, used in high amounts. Still, melatonin is not recommended in Norway for use in this age group because of insufficient data on safety and efficacy. A threefold increase in hypnotic drugs among females from 13 to 17 years of age warrants attention.

Prescription drug use among pregnant women in opioid Maintenance Treatment

AIMS This study describes the use of prescribed drugs among women in opioid maintenance treatment (OMT) prior to, and during, pregnancy. DESIGN This cohort study was based on data from two nationwide databases: the Medical Birth Registry of Norway and the Norwegian Prescription Database. SETTING Norway, 2004-2010. PARTICIPANTS OMT drugs were dispensed to 138 women with 159 pregnancies. MEASUREMENTS All prescription drugs dispensed to women in OMT three months prior to, and during, pregnancy were studied. Amounts of benzodiazepines, z-hypnotics and opioid analgesics dispensed during pregnancy were studied and bivariate analysis was used to study neonatal outcomes of OMT pregnancies with and without such co-medication. FINDINGS The prevalence of prescription drug use by pregnant OMT women was high both during the three-month period prior to (69%), and during (81%), pregnancy. The proportion of pregnant women that was dispensed anti-infectives (48%) and/or drugs acting on the nervous system (45%) during any time in pregnancy was especially high. In 21%, 15% and 13% of the pregnancies the women were dispensed benzodiazepine anxiolytics, opioid analgesics or benzodiazepine hypnotics respectively. Only 5% of the OMT women were dispensed antidepressants. Malformations were significantly more common among children born to mothers in OMT that received co-medication with opioids, benzodiazepines or z-hypnotics. CONCLUSIONS A higher proportion of women in opioid maintenance treatment in Norway use prescription drugs prior to, and during, pregnancy than pregnant women in the general population. Co-medication with drugs with abuse potential may increase the risk of adverse pregnancy outcomes and this need to be further addressed.

The association between smoking and subsequent repeated use of prescribed opioids among adolescents and young adults--a population-based cohort study.

The use of prescribed opioids for chronic non‐cancer pain is increasing in many countries. It is, therefore, important to investigate predictors for repeated use of opioids in young non‐cancer patients.