Impact of COVID-19 Pandemic on Dispensing of Cardiovascular Drugs in Norway: An Interrupted Time Series Study.

INTRODUCTION: The COVID-19 pandemic resulted in changes in prescription patterns and fillings for certain medications, but little is known about its impact on the dispensing of cardiovascular drugs. METHODS: Trends in dispensing of cardiovascular drugs before and during the pandemic were examined using a population-based cohort in Norway. Using interrupted time series analyses and considering March 1, 2020 as the interruption point, the impact of the pandemic on defined daily dose dispensing of prescribed cardiovascular drugs was estimated in a population of adults with and without pre-existing cardiovascular disease from January 2018 to December 2021. All data were analyzed in 2023. RESULTS: In a total of 4,053,957 adults, 690,910 (17.0%) had pre-existing cardiovascular disease. Prior to the pandemic, there was a significant monthly increase in any cardiovascular drug dispensing among those with pre-existing cardiovascular disease (0.30 defined daily dose per month per adult), including prescription of diuretics, calcium channel blockers, and lipid-modifying agents. After controlling for preinterruption trends, there was a slight decrease in level change immediately after the start of the pandemic (2.5 defined daily dose per month per adult) but an increase in the postinterruption trend (0.06 defined daily dose per month per adult) for dispensing of cardiovascular prescriptions, although these changes were not significant. CONCLUSIONS: Although the COVID-19 pandemic did not appear to result in significant changes in patterns of cardiovascular drug dispensing in Norway, continued access to cardiovascular drugs remains important to prevent further related morbidity.

No impact of prenatal paracetamol and folic acid exposure on cord blood DNA methylation in children with attention-deficit/hyperactivity disorder.

Pharmacoepigenetic studies are important to understand the mechanisms through which medications influence the developing fetus. For instance, we and others have reported associations between prenatal paracetamol exposure and offspring DNA methylation (DNAm). Additionally, folic acid (FA) intake during pregnancy has been associated with DNAm in genes linked to developmental abnormalities. In this study, we aimed to: (i) expand on our previous findings showing differential DNAm associated with long-term prenatal paracetamol exposure in offspring with attention-deficit/hyperactivity disorder (ADHD), and (ii) examine if there is an interaction effect of FA and paracetamol on DNAm in children with ADHD. We used data from the Norwegian Mother, Father and Child Cohort Study (MoBa) and the Medical Birth Registry of Norway (MBRN). We did not identify any impact of paracetamol or any interaction effect of paracetamol and FA on cord blood DNAm in children with ADHD. Our results contribute to the growing literature on prenatal pharmacoepigenetics, but should be replicated in other cohorts. Replication of pharmacoepigenetic studies is essential to ensure robust findings and to increase the clinical relevance of such studies.

Artificial intelligence-driven prediction of COVID-19-related hospitalization and death: a systematic review.

Aim: To perform a systematic review on the use of Artificial Intelligence (AI) techniques for predicting COVID-19 hospitalization and mortality using primary and secondary data sources. Study eligibility criteria: Cohort, clinical trials, meta-analyses, and observational studies investigating COVID-19 hospitalization or mortality using artificial intelligence techniques were eligible. Articles without a full text available in the English language were excluded. Data sources: Articles recorded in Ovid MEDLINE from 01/01/2019 to 22/08/2022 were screened. Data extraction: We extracted information on data sources, AI models, and epidemiological aspects of retrieved studies. Bias assessment: A bias assessment of AI models was done using PROBAST. Participants: Patients tested positive for COVID-19. Results: We included 39 studies related to AI-based prediction of hospitalization and death related to COVID-19. The articles were published in the period 2019-2022, and mostly used Random Forest as the model with the best performance. AI models were trained using cohorts of individuals sampled from populations of European and non-European countries, mostly with cohort sample size <5,000. Data collection generally included information on demographics, clinical records, laboratory results, and pharmacological treatments (i.e., high-dimensional datasets). In most studies, the models were internally validated with cross-validation, but the majority of studies lacked external validation and calibration. Covariates were not prioritized using ensemble approaches in most of the studies, however, models still showed moderately good performances with Area under the Receiver operating characteristic Curve (AUC) values >0.7. According to the assessment with PROBAST, all models had a high risk of bias and/or concern regarding applicability. Conclusions: A broad range of AI techniques have been used to predict COVID-19 hospitalization and mortality. The studies reported good prediction performance of AI models, however, high risk of bias and/or concern regarding applicability were detected.

Effects of prenatal exposure to (es)citalopram and maternal depression during pregnancy on DNA methylation and child neurodevelopment.

Studies assessing associations between prenatal exposure to antidepressants, maternal depression, and offspring DNA methylation (DNAm) have been inconsistent. Here, we investigated whether prenatal exposure to citalopram or escitalopram ((es)citalopram) and maternal depression is associated with differences in DNAm. Then, we examined if there is an interaction effect of (es)citalopram exposure and DNAm on offspring neurodevelopmental outcomes. Finally, we investigated whether DNAm at birth correlates with neurodevelopmental trajectories in childhood. We analyzed DNAm in cord blood from the Norwegian Mother, Father and Child Cohort Study (MoBa) biobank. MoBa contains questionnaire data on maternal (es)citalopram use and depression during pregnancy and information about child neurodevelopmental outcomes assessed by internationally recognized psychometric tests. In addition, we retrieved ADHD diagnoses from the Norwegian Patient Registry and information on pregnancies from the Medical Birth Registry of Norway. In total, 958 newborn cord blood samples were divided into three groups: (1) prenatal (es)citalopram exposed (n = 306), (2) prenatal maternal depression exposed (n = 308), and (3) propensity score-selected controls (n = 344). Among children exposed to (es)citalopram, there were more ADHD diagnoses and symptoms and delayed communication and psychomotor development. We did not identify differential DNAm associated with (es)citalopram or depression, nor any interaction effects on neurodevelopmental outcomes throughout childhood. Trajectory modeling identified subgroups of children following similar developmental patterns. Some of these subgroups were enriched for children exposed to maternal depression, and some subgroups were associated with differences in DNAm at birth. Interestingly, several of the differentially methylated genes are involved in neuronal processes and development. These results suggest DNAm as a potential predictive molecular marker of later abnormal neurodevelopmental outcomes, but we cannot conclude whether DNAm links prenatal (es)citalopram exposure or maternal depression with child neurodevelopmental outcomes.

Low reliability of DNA methylation across Illumina Infinium platforms in cord blood: implications for replication studies and meta-analyses of prenatal exposures.

BACKGROUND: There is an increasing interest in the role of epigenetics in epidemiology, but the emerging research field faces several critical biological and technical challenges. In particular, recent studies have shown poor correlation of measured DNA methylation (DNAm) levels within and across Illumina Infinium platforms in various tissues. In this study, we have investigated concordance between 450 k and EPIC Infinium platforms in cord blood. We could not replicate our previous findings on the association of prenatal paracetamol exposure with cord blood DNAm, which prompted an investigation of cross-platform DNAm differences. RESULTS: This study is based on two DNAm data sets from cord blood samples selected from the Norwegian Mother, Father and Child Cohort Study (MoBa). DNAm of one data set was measured using the 450 k platform and the other data set was measured using the EPIC platform. Initial analyses of the EPIC data could not replicate any of our previous significant findings in the 450 k data on associations between prenatal paracetamol exposure and cord blood DNAm. A subset of the samples (n = 17) was included in both data sets, which enabled analyses of technical sources potentially contributing to the negative replication. Analyses of these 17 samples with repeated measurements revealed high per-sample correlations ([Formula: see text] 0.99), but low per-CpG correlations ([Formula: see text] ≈ 0.24) between the platforms. 1.7% of the CpGs exhibited a mean DNAm difference across platforms > 0.1. Furthermore, only 26.7% of the CpGs exhibited a moderate or better cross-platform reliability (intra-class correlation coefficient ≥ 0.5). CONCLUSION: The observations of low cross-platform probe correlation and reliability corroborate previous reports in other tissues. Our study cannot determine the origin of the differences between platforms. Nevertheless, it emulates the setting in studies using data from multiple Infinium platforms, often analysed several years apart. Therefore, the findings may have important implications for future epigenome-wide association studies (EWASs), in replication, meta-analyses and longitudinal studies. Cognisance and transparency of the challenges related to cross-platform studies may enhance the interpretation, replicability and validity of EWAS results both in cord blood and other tissues, ultimately improving the clinical relevance of epigenetic epidemiology.

Prenatal medication exposure and epigenetic outcomes: a systematic literature review and recommendations for prenatal pharmacoepigenetic studies.

When used during pregnancy, analgesics and psychotropics pass the placenta to enter the foetal circulation and may induce epigenetic modifications. Where such modifications occur and whether they disrupt normal foetal developme nt, are currently unanswered questions. This field of prenatal pharmacoepigenetics has received increasing attention, with several studies reporting associations between in utero medication exposure and offspring epigenetic outcomes. Nevertheless, no recent systematic review of the literature is available. Therefore, the objectives of this review were to (i) provide an overview of the literature on the association of prenatal exposure to psychotropics a nd analgesics with epigenetic outcomes, and (ii) suggest recommendations for future studies within prenatal pharmacoepigenetics. We performed systematic literature searches in five databases. The eligible studies assessed human prenatal exposure to psychotropics or analgesics, with epigenetic analyses of offspring tissue as an outcome. We identified 18 eligible studies including 4,419 neonates exposed to either antidepressants, antiepileptic drugs, paracetamol, acetylsalicylic acid, or methadone. The epigenetic outcome in all studies was DNA methylation in cord blood, placental tissue or buccal cells. Although most studies found significant differences in DNA methylation upon medication exposure, almost no differences were persistent across studies for similar medications and sequencing methods. The reviewed studies were challenging to compare due to poor transparency in reporting, and heterogeneous methodology, design, genome coverage, and statistical modelling. We propose 10 recommendations for future prenatal pharmacoepigenetic studies considering both epidemiological and epigenetic perspectives. These recommendations may improve the quality, comparability, and clinical relevance of such studies. PROSPERO registration ID: CRD42020166675.

Use of interrupted time-series analysis to characterise antibiotic prescription fills across pregnancy: a Norwegian nationwide cohort study.

OBJECTIVES: Antibiotics are the most frequently prescribed medications for pregnant and breastfeeding women. We applied interrupted time-series analysis (ITSA) to describe antibiotic prescription fills patterns in pregnant women and examined recurrent antibiotic fills in subsequent pregnancies. DESIGNS: A population-based drug utilisation study. SETTING: Norwegian primary care. PARTICIPANTS: 653 058 pregnancies derived from Medical Birth Registry of Norway linked to the Norwegian Prescription Database (2006-2016). MAIN OUTCOME MEASURE: Proportion of pregnancies exposed to antibiotics aggregated by week in pregnancy time windows. STATISTICAL ANALYSES: We descriptively analysed antibiotic prescription fills patterns and components in pregnant women. The changes in antibiotic fills in pregnancy time windows were assessed using ITSA. Interruptions points at week 4 to week 7 into pregnancy and delivery were used. Factors associated with antibiotic fills during pregnancy were identified using generalised estimating equations for Poisson regression. Recurrent antibiotic use was estimated using proportion of women who filled antibiotic prescription in a subsequent pregnancy. RESULTS: Antibiotics were filled in 27.6% pregnancies. The ITSA detected an immediate decrease of 0.07 percentage points (95% CI -0.13 to -0.01) in the proportion of exposed pregnancies at 4 weeks after conception, mainly among women taking folic acid before pregnancy. This proportion increased shortly after delivery (immediate change=1.61 percentage points (95% CI 0.31 to 2.91)) then decreased gradually afterwards (change in slope=-0.19 percentage points, 95% CI -0.34 to -0.05)). The strongest factor associated with antibiotic fills during pregnancy was having recurrent urinary tract infections (adjusted OR=2.65, 95% CI 2.59 to 2.72). Women who had filled antibiotics during a pregnancy were up to three times more likely to fill antibiotics in the subsequent pregnancies. CONCLUSIONS: ITSA highlighted important impact of pregnancy and delivery on antibiotic fillings. Having antibiotic fills in a pregnancy was associated with recurrent antibiotic fills in subsequent ones.

Genetic Susceptibility to Drug Teratogenicity: A Systematic Literature Review.

Since the 1960s, drugs have been known to cause teratogenic effects in humans. Such teratogenicity has been postulated to be influenced by genetics. The aim of this review was to provide an overview of the current knowledge on genetic susceptibility to drug teratogenicity in humans and reflect on future directions within the field of genetic teratology. We focused on 12 drugs and drug classes with evidence of teratogenic action, as well as 29 drugs and drug classes with conflicting evidence of fetal safety in humans. An extensive literature search was performed in the PubMed and EMBASE databases using terms related to the drugs of interest, congenital anomalies and fetal development abnormalities, and genetic variation and susceptibility. A total of 29 studies were included in the final data extraction. The eligible studies were published between 1999 and 2020 in 10 different countries, and comprised 28 candidate gene and 1 whole-exome sequencing studies. The sample sizes ranged from 20 to 9,774 individuals. Several drugs were investigated, including antidepressants (nine studies), thalidomide (seven studies), antiepileptic drugs (five studies), glucocorticoids (four studies), acetaminophen (two studies), and sex hormones (estrogens, one study; 17-alpha hydroxyprogesterone caproate, one study). The main neonatal phenotypic outcomes included perinatal complications, cardiovascular congenital anomalies, and neurodevelopmental outcomes. The review demonstrated that studies on genetic teratology are generally small, heterogeneous, and exhibit inconsistent results. The most convincing findings were genetic variants in SLC6A4, MTHFR, and NR3C1, which were associated with drug teratogenicity by antidepressants, antiepileptics, and glucocorticoids, respectively. Notably, this review demonstrated the large knowledge gap regarding genetic susceptibility to drug teratogenicity, emphasizing the need for further efforts in the field. Future studies may be improved by increasing the sample size and applying genome-wide approaches to promote the interpretation of results. Such studies could support the clinical implementation of genetic screening to provide safer drug use in pregnant women in need of drugs.

Does progestin-only contraceptive use after pregnancy affect recovery from pelvic girdle pain? A prospective population study.

OBJECTIVE: To estimate associations of progestin-only contraceptives with persistent pelvic girdle pain 18 months after delivery. METHODS: Prospective population based cohort study during the years 2003-2011. We included 20,493 women enrolled in the Norwegian Mother and Child Cohort Study who reported pelvic girdle pain in pregnancy week 30. Data were obtained by 3 self-administered questionnaires and the exposure was obtained by linkage to the Prescription Database of Norway. The outcome was pelvic girdle pain 18 months after delivery. RESULTS: Pelvic girdle pain 18 months after delivery was reported by 9.7% (957/9830) of women with dispense of a progestin-only contraceptive and by 10.5% (1114/10,663) of women without dispense (adjusted odds ratio 0.93; 95% CI 0.84-1.02). In sub-analyses, long duration of exposure to a progestin intrauterine device or progestin-only oral contraceptives was associated with reduced odds of persistent pelvic girdle pain (Ptrend = 0.021 and Ptrend = 0.005). Conversely, long duration of exposure to progestin injections and/or a progestin implant was associated with modest increased odds of persistent pelvic girdle pain (Ptrend = 0.046). Early timing of progestin-only contraceptive dispense following delivery (≤3 months) was not significantly associated with persistent pelvic girdle pain. CONCLUSIONS: Our findings suggest a small beneficial effect of progestin intrauterine devices and progestin-only oral contraceptives on recovery from pelvic girdle pain. We cannot completely rule out an opposing adverse effect of exposure to progestin injections and/or progestin implants. However, the modest increased odds of persistent pelvic girdle pain among these users could be a result of unmeasured confounding.