Search

Importance: Understanding the safety profile of medications used in pregnancy is crucial for clinical decision-making. Few studies exist on the associations of exposure to benzodiazepines and benzodiazepine-like hypnotic drugs (z-hypnotics) in pregnancy with pregnancy outcomes., Objective: To determine whether exposure to benzodiazepines or z-hypnotics in pregnancy is associated with greater risk of negative immediate pregnancy outcomes compared with nonexposure., Design, Setting, and Participants: This questionnaire-based cohort study used data from the Norwegian Mother, Father and Child cohort study (MoBa), which also includes data from the Medical Birth Registry of Norway. Pregnant women were recruited from all over Norway from 1999 and 2008. The first child was born in October 1999 and the last in July 2009. This analysis included women who completed 3 questionnaires, twice during pregnancy and once 6 months after delivery. Data analyses were conducted from September to November 2019., Exposures: Self-reported exposure to benzodiazepines or z-hypnotics during pregnancy, characterized in terms of any exposure, timing (ie, early, middle, or late), and duration of exposure., Main Outcomes and Measures: The main outcomes were gestational age at delivery, risk of preterm delivery, birth weight, birth weight relative to gestational age and sex, risk of being small for gestational age, head circumference, Apgar score less than 7 at 5 minutes, and risk of neonatal respiratory distress. Continuous outcomes are reported using effect estimates as mean differences, and binary outcomes are reported using risk ratios., Results: The MoBa study included 114 234 mother-child dyads. This analysis of MoBa data includes 82 038 singleton pregnancies among 69 434 unique women. Mean (SD) maternal age was 30.2 (4.5) years, and 37 641 pregnancies (45.9%) were in primiparous women. Exposure to benzodiazepines or z-hypnotics was reported in 679 pregnancies (0.8%). After adjusting for all measured baseline and postbaseline confounders, benzodiazepine or z-hypnotic use during pregnancy was associated with lower birth weight (mean difference, -79.3 [95% CI, -126.7 to -31.9] g), lower gestational age at birth (mean difference, -2.1 [95% CI, -3.3 to -0.9] days), and higher risk of preterm birth (risk ratio, 1.41 [95% CI, 1.03 to 1.94]). We found no significant association of exposure to benzodiazepines or z-hypnotics with the child's birth weight relative to gestational age and sex (z score), or any of the other immediate birth outcomes., Conclusions and Relevance: These findings suggest that the magnitude of the association of exposure to benzodiazepines or z-hypnotics with gestational age is not necessarily clinically significant. The absence of an association of exposure to benzodiazepines or z-hypnotics with z score for birth weight relative to gestational age and sex suggests that association of exposure to benzodiazepines or z-hypnotics with birth weight could be explained by earlier delivery rather than impaired intrauterine growth.

Importance: The reproductive safety of benzodiazepine/z-hypnotic exposure on child longer-term developmental risks remains unresolved., Objective: To quantify the association of motor, communication, and attention-deficit/hyperactivity disorder (ADHD) symptoms in preschoolers with gestational benzodiazepine/z-hypnotic exposure by timing and duration and coexposure to opioids or antidepressants., Design, Setting, and Participants: Nationwide, population-based Norwegian Mother and Child Cohort Study, recruiting pregnant women from 1999 to 2008, with child follow-up from ages 6, 18, and 36 months to ages 5, 7, and 8 years. Follow-up of teenagers is ongoing. The study included women with depressive/anxiety (n = 4195), sleeping (n = 5260), or pain-related (n = 26 631) disorders before and/or during pregnancy., Exposures: For the timing analyses, children exposed to benzodiazepines/z-hypnotics in midpregnancy (weeks 17-28) or late pregnancy (week 29 or later) vs those born to nonmedicated women. For the duration and coexposure analyses, benzodiazepine/z-hypnotic treatment for multiple 4-week intervals vs 1 and co-use of benzodiazepine/z-hypnotic with opioids or antidepressants vs sole benzodiazepine/z-hypnotic use., Main Outcomes and Measures: Parent-reported motor and communication skills (Ages and Stages Questionnaires) and ADHD symptoms (Conners' Parent Rating Scale-Revised) at child median age of 5.1 years (interquartile range, 5.0-5.3 years) as standardized mean scores. General linear propensity score-adjusted and marginal structural models were fitted. Analyses were stratified by maternal disorder., Results: Of 41 146 eligible pregnancy-child dyads, 36 086 children (18 330 boys and 17 756 girls) were included, of whom 283 (0.8%) were prenatally exposed to benzodiazepines/z-hypnotics (134 in the depressive/anxiety, 60 in the sleeping, and 89 in the pain-related disorders). There was no increased risk for greater ADHD symptoms or fine motor deficits after intrauterine benzodiazepine/z-hypnotic exposure at different time points. Children born to women with depressive/anxiety disorders who took benzodiazepines/z-hypnotics in late pregnancy had greater gross motor (weighted β, 0.67; 95% CI, 0.21-1.13) and communication (weighted β, 0.35; 95% CI, 0.04-0.65) deficits than unexposed children. There was no evidence for substantial duration or coexposure associations., Conclusions and Relevance: These findings suggest no substantial detrimental risk on child fine motor and ADHD symptoms after prenatal benzodiazepine/z-hypnotic exposure alone or in combination with opioids or antidepressants. Residual confounding by indication and/or a higher drug dose regimen among women with anxiety/depression may explain the moderate association of gross motor and communication deficits with late-pregnancy benzodiazepine/z-hypnotic use.

Benzodiazepine-like drugs (z-hypnotics) are the most commonly used drugs for treatment of insomnia in Norway. Z-hypnotics are recommended for short-term treatment not exceeding 4 weeks. We aimed to study the use of z-hypnotics in the adult population in Norway with focus on recurrent use in new users, treatment intensity and co-medication with benzodiazepines and opioids in long-term users. Data were obtained from the Norwegian Prescription Database. New users in 2009 were followed through 2013. Recurrent z-hypnotic use was defined as new fillings at least once in each of the four 365-day follow-up periods. Age groups of 18-39, 40-64 and 65+ years were analysed separately for men and women. In 2013, 354,571 (8.9%) of the population filled at least one prescription of z-hypnotics and the prevalence was relatively stable over time. Among the 92,911 new users of z-hypnotics in 2009, 13,996 (16.8%) received z-hypnotics all four 365-day periods of follow-up. In these long-term recurrent users, the treatment intensity was high already the second year, with mean annual amounts of 199 and 169 DDDs per patient in men and women, respectively. The interquartile differences were greatest in the youngest age group. 27.9% of the long-term recurrent users of z-hypnotics used benzodiazepines the fourth year and 33.9% used opioids. The proportions with co-medication increased with level of z-hypnotic treatment intensity. Overall, many z-hypnotic users had medicines dispensed for longer periods than recommended, and co-medications with drugs that may reinforce the central depressing and intoxicating effects were common., (© 2016 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)

The aims were, for the entire Norwegian population aged 4-17 years, to study the prevalence of melatonin use during 2004-2012, recurrent use in incident users and psychiatric and neurological morbidity in recurrent users. Data on dispensed melatonin were retrieved from the Norwegian Prescription Database and linked to diagnostic data from the Norwegian Patient Register. Outcome measures were the following: 1-year prevalence of use, proportion of recurrent use (use over three consecutive 365-day periods among incident users in 2009) and annual number of milligrams and number of prescriptions dispensed in recurrent users. The prevalence of registered ICD-10 diagnoses during the period of 2008-2012 was given for the recurrent users. The prevalence of melatonin use increased annually in both genders during 2004-2012 (boys: 3.4-11.0 per 1000; girls: 1.5-7.7 per 1000). Twenty-nine per cent of boys and 23% of girls were recurrent melatonin users, with highest level of recurrent use among the youngest (aged 4-8 years; boys: 47%, girls: 42%). In the third year, the median annual amount of melatonin dispensed was 1080 (IQR 586-1800) milligrams in boys and 900 (IQR 402-1620) milligrams in girls. Among recurrent users, 91% had a diagnosis of either psychiatric (84%) or neurological (32%) disorder. Off-label recurrent use of melatonin seems to have acquired a role mainly in treating secondary sleep problems in children and adolescents with psychiatric and neurological disorders. Once melatonin has been started, a large proportion of patients continue for at least 3 years, in doses corresponding to daily use in the majority., (© 2015 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)

Purpose: The aim of the study was to examine if there was an association between use of anxiolytics and hypnotics in pregnancy and language competence in the offspring at age 3 years., Methods: The Norwegian Mother and Child Cohort Study (MoBa) is a prospective pregnancy cohort where the mothers were asked to report on their medication use at pregnancy week 17-18, 30, and at 6 months postpartum. A woman was defined as a user of anxiolytics and hypnotics during pregnancy if she had reported use of benzodiazepines or benzodiazepine-related drugs during pregnancy. Children's language competence was measured at age three by maternal report on a validated language grammar scale. We used ordinal logistic regression with estimated standard errors allowing for clustering of multiple pregnancies., Results: Forty-five thousand and two hundred sixty-six women with 51,748 pregnancies were included in the study. The women reported use of anxiolytics and/or hypnotics in 395 pregnancies (0.8 %). The odds ratios of being in a group with lower language competence were 1.2 (0.9-1.5) and 1.7 (1.0-2.8) for short-term and long-term anxiolytics and hypnotics use, respectively. When adjusting for SSRI use during pregnancy, the odds ratios were 1.1 (0.83-1.41) and 1.4 (0.84-2.33), respectively. Children whose mothers took no anxiolytics and hypnotics during or before pregnancy were reference group., Conclusion: The results refute any strong association between prenatal use of anxiolytics and hypnotics and lower language competence in the offspring at age 3 years.

Purpose: The study aimed to describe the dispensing of benzodiazepines and benzodiazepine-related drugs (z-hypnotics) to pregnant women and to study the characteristics of these women and the extent of co-medication., Methods: A population-based cohort study was conducted based on the linkage of nationwide registries: the Medical Birth Registry of Norway and the Norwegian Prescription Database. The data covers dispensed drugs to women 3 months prior to, during and after pregnancy. The study population consisted of 345,703 singleton pregnancies during a period starting 1 April 2004 or later and ending before 1 January 2011., Results: In 5,135 (1.5 %) of the pregnancies, the women were dispensed a benzodiazepine or z-hypnotic at least once. Of these, 68.5 % filled just one prescription for the duration of the pregnancy. Prevalence was lower in pregnancy than before and after pregnancy. The median total amount of benzodiazepines and/or z-hypnotics dispensed during pregnancy was 15 defined daily doses (DDDs), while the 25 % receiving the largest amounts got 40 DDDs or more. Five hundred eleven women, the 10 % that were prescribed the largest amounts during pregnancy, received a median amount of 220 DDDs. Women receiving these drugs were older, more often smokers, without a partner and suffering from chronic disease. Of the medicated pregnant women, 19.6 % and 19.3 % were also prescribed an opioid and antidepressant, respectively., Conclusions: The use of benzodiazepines and z-hypnotic drugs during pregnancy was not very prevalent in Norway. However, our findings imply that there is a substantial number of pregnancies where these drugs are dispensed often and/or in large quantities and where co-medication occurred.

Objective: To describe the dispensing of the hypnotic alimemazine to children aged 0-3 years and investigate the association between dispensing of alimemazine to children and dispensed hypnotics to their parents., Design: An observational cohort study linking information from the Medical Birth Registry of Norway and the Norwegian Prescription Database. Hypnotics dispensed to parents in a 1-year period before pregnancy was associated with dispensed alimemazine for children aged 0-3 years., Patients and Setting: All children born in Norway in 2008 (N=59 325) and their mothers and fathers were included., Main Outcome Measures: Dispensed alimemazine to children during the first 3 years of life., Results: Three percent of children received alimemazine. Dispensed hypnotics to mothers increased the risk of the child receiving a prescription for alimemazine, OR of 2.3 (1.7-3.0) for boys and 1.7 (1.2-2.4) for girls. When both parents had been dispensed prescriptions for hypnotics, the risk increased nearly threefold. A dispensed alimemazine prescription was also associated with dispensed prescriptions for antidepressants to both mother and father, mother's smoking, the child's gender and child's prescriptions for antibiotics, respiratory drugs and dermatological steroids., Conclusions: Dispensed alimemazine to children under 3 was associated with parents' previous use of hypnotics, indicating that factors other than the child's health influence the use of hypnotic drugs in infancy and toddler years. The frequent usage of alimemazine in children below 3 years and the association with parents' use of hypnotics should concern prescribing doctors.

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., (© 2012 The Authors, Addiction © 2012 Society for the Study of Addiction.)

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.

Background: The various benzodiazepines have essentially the same mechanism of action and differ from one another primarily through differences in pharmacokinetics. There is no pharmacological basis for using more than one benzodiazepine for the same patient. The purpose of the study was to examine the occurence of co-medication with different types of benzodiazepines in Norway., Material and Method: Data were obtained from the Norwegian Prescription Database. Patients who received at least one benzodiazepine in 2008 were included (n = 299,185). The percentage of users who were co-medicated with at least two different benzodiazepines and the amounts prescribed were calculated and stratified by gender and age., Results: It is highly probably that 27,861 (14,6%) of patients who received at least two benzodiazepines in the course of 2008 used two different benzodiazepines simultaneously. 13,267 (6.9%) of the patients were prescribed at least two different benzodiazepines on the same prescription. A larger number of women were co-medicated with different benzodiazepines, but the proportion of comedication was higher in men than in women, and most frequent in the age group 18-49 years., Interpretation: There is an extensive and unfortunate prescription practice whereby the same patient is prescribed different benzodiazepines that are used concurrently. Patients who use different benzodiazepines concurrently are mainly prescribed these by one and the same doctor.