COVID-19 vaccine uptake among children and adolescents in Norway: A comprehensive registry-based cohort study of over 800,000 individuals.

Factors related with COVID-19 vaccine uptake in children and adolescents in Norway remain unclear, despite this being useful knowledge for future pandemic preparedness. This study aimed to comprehensively examine individual and familial factors associated with vaccine uptake in children and adolescents in Norway. We utilized nationwide registry-data from various health registries and Statistics Norway, encompassing all children and adolescents living in Norway during the pandemic, until 31-Dec-2022. Vaccine uptake is defined as receiving at least one dose of COVID-19 vaccine. We employed a forward stepwise logistic regression model and a random forest machine-learning algorithm to explore the relationship between vaccine uptake and socio-cultural, demographic, and health-related factors. We included 423,548 5-11-year-olds, 269,830 12-15-year-olds, and 120,854 16-17-year-olds. Vaccine uptake in these three groups was respectively 2.6 %, 73.3 %, and 87.3 %. Factors associated with vaccine uptake varied by age group. In youngest children, immigrant background (Odds-ratio (OR) = 1.58, 95 % confidence interval (CI) (1.14-2.19)), born extremely preterm (OR = 2.38, 95 % CI (1.60-3.54)), having risk of severe COVID-19 (OR = 5.40, 95 % CI (4.69-6.23) and maternal COVID-19 vaccination (OR = 6.34, 95 % CI (5.35-7.53)) were positively associated with vaccine uptake. The latter two factors were also strongly, positively associated with vaccine uptake in 12-15-year-olds, while previous SARS-CoV-2 infection was negatively associated (OR = 0.12, 95 % CI (0.11-0.14). Similar findings were observed in 16-17-year-olds. COVID-19 vaccine uptake differed markedly by age group, and major associated factors included socio-demographics and parental COVID-19 vaccination status, prior SARS-CoV-2 infection, but also being born premature and having moderate or high risk of severe COVID-19.

Identification and characterization of migraine in pregnancy: A Norwegian registry-based cohort study.

BACKGROUND: Migraine is common in women of reproductive age. Migraine's episodic manifestation and acute and preventive pharmacological treatment options challenge studying drug safety for this condition during pregnancy. To improve such studies, we aimed to develop algorithms to identify and characterize migraines in electronic healthcare registries and to assess the level of care. METHODS: We linked four registries to detect pregnancies from 2009-2018 and used three algorithms for migraine identification: i) diagnostic codes, ii) triptans dispensed, and iii) a combination of both. We assessed migraine severity using dispensed drugs as proxies. ICD-10 diagnostic subcodes of migraine (G43) allowed the allocation of four subtypes: complicated and/or status migrainosus; with aura; without aura; other/unspecified. RESULTS: We included 535,089 pregnancies in 367,908 women with available one-year lookback. The prevalence of migraines identified was 2.9%-4.3% before, and 0.8%-1.5% during pregnancy, depending on algorithm used. Pregnant women with migraine were mostly managed in primary care. CONCLUSIONS: Primary care data in combination with drug dispensation records were instrumental for identification of migraine in electronic healthcare registries. Data from secondary care and drug dispensations allow better characterization of migraines. Jointly, these algorithms may contribute to improved perinatal pharmacoepidemiological studies in this population by addressing confounding by maternal migraine indication.

The role of COVID-19 vaccines in preventing post-COVID-19 thromboembolic and cardiovascular complications.

OBJECTIVE: To study the association between COVID-19 vaccination and the risk of post-COVID-19 cardiac and thromboembolic complications. METHODS: We conducted a staggered cohort study based on national vaccination campaigns using electronic health records from the UK, Spain and Estonia. Vaccine rollout was grouped into four stages with predefined enrolment periods. Each stage included all individuals eligible for vaccination, with no previous SARS-CoV-2 infection or COVID-19 vaccine at the start date. Vaccination status was used as a time-varying exposure. Outcomes included heart failure (HF), venous thromboembolism (VTE) and arterial thrombosis/thromboembolism (ATE) recorded in four time windows after SARS-CoV-2 infection: 0-30, 31-90, 91-180 and 181-365 days. Propensity score overlap weighting and empirical calibration were used to minimise observed and unobserved confounding, respectively.Fine-Gray models estimated subdistribution hazard ratios (sHR). Random effect meta-analyses were conducted across staggered cohorts and databases. RESULTS: The study included 10.17 million vaccinated and 10.39 million unvaccinated people. Vaccination was associated with reduced risks of acute (30-day) and post-acute COVID-19 VTE, ATE and HF: for example, meta-analytic sHR of 0.22 (95% CI 0.17 to 0.29), 0.53 (0.44 to 0.63) and 0.45 (0.38 to 0.53), respectively, for 0-30 days after SARS-CoV-2 infection, while in the 91-180 days sHR were 0.53 (0.40 to 0.70), 0.72 (0.58 to 0.88) and 0.61 (0.51 to 0.73), respectively. CONCLUSIONS: COVID-19 vaccination reduced the risk of post-COVID-19 cardiac and thromboembolic outcomes. These effects were more pronounced for acute COVID-19 outcomes, consistent with known reductions in disease severity following breakthrough versus unvaccinated SARS-CoV-2 infection.

Impact of the early COVID-19 pandemic on adult mental health-related dispensed medications, hospitalizations and specialist outpatient visits in Norway and Sweden: Interrupted time series analysis.

AIMS: Norway and Sweden had different early pandemic responses that may have impacted mental health management. The aim was to assess the impact of the early COVID-19 pandemic on mental health-related care. METHODS: We used national registries in Norway and Sweden (1 January 2018-31 December 2020) to define 2 cohorts: (i) general adult population; and (ii) mental health adult population. Interrupted times series regression analyses evaluated step and slope changes compared to prepandemic levels for monthly rates of medications (antidepressants, antipsychotics, anxiolytics, hypnotics/sedatives, lithium, opioid analgesics, psychostimulants), hospitalizations (for anxiety, bipolar, depressive/mood, eating and schizophrenia/delusional disorders) and specialist outpatient visits. RESULTS: In Norway, immediate reductions occurred in the general population for medications (-12% antidepressants to -7% hypnotics/sedatives) except for antipsychotics; and hospitalizations (-33% anxiety disorders to -17% bipolar disorders). Increasing slope change occurred for all medications except psychostimulants (+1.1%/month hypnotics/sedatives to +1.7%/month antidepressants); and hospitalization for anxiety disorders (+5.5%/month), depressive/mood disorders (+1.7%/month) and schizophrenia/delusional disorders (+2%/month). In Sweden, immediate reductions occurred for antidepressants (-7%) and opioids (-10%) and depressive/mood disorder hospitalizations (-11%) only with increasing slope change in psychostimulant prescribing of (0.9%/month). In contrast to Norway, increasing slope changes occurred in specialist outpatient visits for depressive/mood disorders, eating disorders and schizophrenia/delusional disorders (+1.5, +1.9 and +2.3%/month, respectively). Similar changes occurred in the pre-existing mental health cohorts. CONCLUSION: Differences in early COVID-19 policy response may have contributed to differences in adult mental healthcare provision in Norway and Sweden.

COVID-19 and pregnancy: A European study on pre- and post-infection medication use.

PURPOSE: The COVID-19 pandemic has impacted medication needs and prescribing practices, including those affecting pregnant women. Our goal was to investigate patterns of medication use among pregnant women with COVID-19, focusing on variations by trimester of infection and location. METHODS: We conducted an observational study using six electronic healthcare databases from six European regions (Aragon/Spain; France; Norway; Tuscany, Italy; Valencia/Spain; and Wales/UK). The prevalence of primary care prescribing or dispensing was compared in the 30-day periods before and after a positive COVID-19 test or diagnosis. RESULTS: The study included 294,126 pregnant women, of whom 8943 (3.0%) tested positive for, or were diagnosed with, COVID-19 during their pregnancy. A significantly higher use of antithrombotic medications was observed particularly after COVID-19 infection in the second and third trimesters. The highest increase was observed in the Valencia region where use of antithrombotic medications in the third trimester increased from 3.8% before COVID-19 to 61.9% after the infection. Increases in other countries were lower; for example, in Norway, the prevalence of antithrombotic medication use changed from around 1-2% before to around 6% after COVID-19 in the third trimester. Smaller and less consistent increases were observed in the use of other drug classes, such as antimicrobials and systemic corticosteroids. CONCLUSION: Our findings highlight the substantial impact of COVID-19 on primary care medication use among pregnant women, with a marked increase in the use of antithrombotic medications post-COVID-19. These results underscore the need for further research to understand the broader implications of these patterns on maternal and neonatal/fetal health outcomes.

Drug utilisation in children and adolescents before and after the start of the COVID-19 pandemic: Interrupted time-series analyses in three European countries.

BACKGROUND: The COVID-19 pandemic has affected children and adolescents in several ways, including worsened mental health, improvement of asthma, and increases in diabetes ketoacidosis. Less is known about how medication use in children and adolescents has been affected by the pandemic. OBJECTIVES: To explore how the COVID-19 pandemic affected drug utilisation in children and adolescents in Norway, Sweden, and Italy, by child age. METHODS: We conducted a longitudinal drug utilisation study among all children and adolescents (<18 years old) in Norway and Sweden and a nationwide paediatric database covering 3% of the paediatric population in Italy. We conducted an interrupted time-series analysis from January 2018 to December 2021, with March 2020 as the interruption point. Dispensing or prescription rates of antidepressants, anxiolytics, sleep medications, attention-deficit/hyperactivity disorder (ADHD) medications, insulin, and asthma medications were examined. RESULTS: The study population in January 2018 consisted of 3,455,521 children and adolescents (136,188 from Italy, 1,160,431 from Norway, and 2,158,902 from Sweden). For sleep medications and insulin, there were only minor changes in level or trend in some age groups after March 2020. For asthma medications, the pandemic was associated with an immediate decrease in dispensing in Norway and Sweden (range of change in level: -19.2 to -3.7 dispensings per 1000 person-months), and an increasing trend in all countries afterward (range of change in trend: 0.3-6.4 dispensings per 1000 person-months), especially for the youngest age groups. Among adolescents, the pandemic was associated with an increased trend for ADHD medications, antidepressants, and anxiolytics in Norway and Sweden, but not in Italy. CONCLUSIONS: The increasing trend of psychotropic medication dispensing, especially among adolescents after the start of the pandemic, is concerning and should be investigated further. Aside from a temporary effect on asthma medication dispensing, the pandemic did not greatly affect the dispensing of the medications investigated.

The effectiveness of COVID-19 vaccines to prevent long COVID symptoms: staggered cohort study of data from the UK, Spain, and Estonia.

BACKGROUND: Although vaccines have proved effective to prevent severe COVID-19, their effect on preventing long-term symptoms is not yet fully understood. We aimed to evaluate the overall effect of vaccination to prevent long COVID symptoms and assess comparative effectiveness of the most used vaccines (ChAdOx1 and BNT162b2). METHODS: We conducted a staggered cohort study using primary care records from the UK (Clinical Practice Research Datalink [CPRD] GOLD and AURUM), Catalonia, Spain (Information System for Research in Primary Care [SIDIAP]), and national health insurance claims from Estonia (CORIVA database). All adults who were registered for at least 180 days as of Jan 4, 2021 (the UK), Feb 20, 2021 (Spain), and Jan 28, 2021 (Estonia) comprised the source population. Vaccination status was used as a time-varying exposure, staggered by vaccine rollout period. Vaccinated people were further classified by vaccine brand according to their first dose received. The primary outcome definition of long COVID was defined as having at least one of 25 WHO-listed symptoms between 90 and 365 days after the date of a PCR-positive test or clinical diagnosis of COVID-19, with no history of that symptom 180 days before SARS-Cov-2 infection. Propensity score overlap weighting was applied separately for each cohort to minimise confounding. Sub-distribution hazard ratios (sHRs) were calculated to estimate vaccine effectiveness against long COVID, and empirically calibrated using negative control outcomes. Random effects meta-analyses across staggered cohorts were conducted to pool overall effect estimates. FINDINGS: A total of 1 618 395 (CPRD GOLD), 5 729 800 (CPRD AURUM), 2 744 821 (SIDIAP), and 77 603 (CORIVA) vaccinated people and 1 640 371 (CPRD GOLD), 5 860 564 (CPRD AURUM), 2 588 518 (SIDIAP), and 302 267 (CORIVA) unvaccinated people were included. Compared with unvaccinated people, overall HRs for long COVID symptoms in people vaccinated with a first dose of any COVID-19 vaccine were 0·54 (95% CI 0·44-0·67) in CPRD GOLD, 0·48 (0·34-0·68) in CPRD AURUM, 0·71 (0·55-0·91) in SIDIAP, and 0·59 (0·40-0·87) in CORIVA. A slightly stronger preventative effect was seen for the first dose of BNT162b2 than for ChAdOx1 (sHR 0·85 [0·60-1·20] in CPRD GOLD and 0·84 [0·74-0·94] in CPRD AURUM). INTERPRETATION: Vaccination against COVID-19 consistently reduced the risk of long COVID symptoms, which highlights the importance of vaccination to prevent persistent COVID-19 symptoms, particularly in adults. FUNDING: National Institute for Health and Care Research.

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.

Transfer of cetirizine/levocetirizine into human breast milk and estimation of drug exposure to infants through breastfeeding: A human lactation study from the ConcePTION project.

Data on drug transfer into human breast milk are sparse. This study aimed to quantify concentrations of cetirizine and levocetirizine in breast milk and to estimate drug exposure to infants. Breastfeeding women at least 8 weeks postpartum and using cetirizine or its pure (R)-enantiomer levocetirizine were eligible to participate. Breast milk samples were collected at six predefined times during a dose interval (0, 2, 4, 8, 12 and 24 h after drug intake) at steady state. Infant drug exposure was estimated by calculating the absolute infant dose (AID) and the weight-adjusted relative infant dose (RID). In total, 32 women were eligible for final inclusion, 31 women using cetirizine and one woman using levocetirizine. Means of the individual maximum and average cetirizine milk concentrations were 41.0 and 16.8 µg/L, respectively. Maximum concentrations occurred on average 2.4 h after intake, and the mean half-life in milk was 7.0 h. Estimated AID and RID for cetirizine in a day were 2.5 µg/kg and 1.9%, respectively. The corresponding values for levocetirizine were 1.1 µg/kg and 1.9%. No severe adverse events were reported. Our findings demonstrate that the transfer of cetirizine and levocetirizine into breast milk is low and compatible with breastfeeding.

Machine learning-driven development of a disease risk score for COVID-19 hospitalization and mortality: a Swedish and Norwegian register-based study.

Aims: To develop a disease risk score for COVID-19-related hospitalization and mortality in Sweden and externally validate it in Norway. Method: We employed linked data from the national health registries of Sweden and Norway to conduct our study. We focused on individuals in Sweden with confirmed SARS-CoV-2 infection through RT-PCR testing up to August 2022 as our study cohort. Within this group, we identified hospitalized cases as those who were admitted to the hospital within 14 days of testing positive for SARS-CoV-2 and matched them with five controls from the same cohort who were not hospitalized due to SARS-CoV-2. Additionally, we identified individuals who died within 30 days after being hospitalized for COVID-19. To develop our disease risk scores, we considered various factors, including demographics, infectious, somatic, and mental health conditions, recorded diagnoses, and pharmacological treatments. We also conducted age-specific analyses and assessed model performance through 5-fold cross-validation. Finally, we performed external validation using data from the Norwegian population with COVID-19 up to December 2021. Results: During the study period, a total of 124,560 individuals in Sweden were hospitalized, and 15,877 individuals died within 30 days following COVID-19 hospitalization. Disease risk scores for both hospitalization and mortality demonstrated predictive capabilities with ROC-AUC values of 0.70 and 0.72, respectively, across the entire study period. Notably, these scores exhibited a positive correlation with the likelihood of hospitalization or death. In the external validation using data from the Norwegian COVID-19 population (consisting of 53,744 individuals), the disease risk score predicted hospitalization with an AUC of 0.47 and death with an AUC of 0.74. Conclusion: The disease risk score showed moderately good performance to predict COVID-19-related mortality but performed poorly in predicting hospitalization when externally validated.

Multi-omics approach reveals dysregulated genes during hESCs neuronal differentiation exposure to paracetamol.

Prenatal paracetamol exposure has been associated with neurodevelopmental outcomes in childhood. Pharmacoepigenetic studies show differences in cord blood DNA methylation between unexposed and paracetamol-exposed neonates, however, causality and impact of long-term prenatal paracetamol exposure on brain development remain unclear. Using a multi-omics approach, we investigated the effects of paracetamol on an in vitro model of early human neurodevelopment. We exposed human embryonic stem cells undergoing neuronal differentiation with paracetamol concentrations corresponding to maternal therapeutic doses. Single-cell RNA-seq and ATAC-seq integration identified paracetamol-induced chromatin opening changes linked to gene expression. Differentially methylated and/or expressed genes were involved in neurotransmission and cell fate determination trajectories. Some genes involved in neuronal injury and development-specific pathways, such as KCNE3, overlapped with differentially methylated genes previously identified in cord blood associated with prenatal paracetamol exposure. Our data suggest that paracetamol may play a causal role in impaired neurodevelopment.

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.

Evolution of National Guidelines on Medicines Used to Treat COVID-19 in Pregnancy in 2020-2022: A Scoping Review.

The lack of inclusion of pregnant women in clinical trials evaluating the effectiveness of medicines to treat COVID-19 has made it difficult to establish evidence-based treatment guidelines for pregnant women. Our aim was to provide a review of the evolution and updates of the national guidelines on medicines used in pregnant women with COVID-19 published by the obstetrician and gynecologists' societies in thirteen countries in 2020-2022. Based on the results of the RECOVERY (Randomized Evaluation of COVID-19 Therapy) trial, the national societies successively recommended against prescribing hydroxychloroquine, lopinavir-ritonavir and azithromycin. Guidelines for remdesivir differed completely between countries, from compassionate or conditional use to recommendation against. Nirmatrelvir-ritonavir was authorized in Australia and the UK only in research settings and was no longer recommended in the UK at the end of 2022. After initial reluctance to use corticosteroids, the results of the RECOVERY trial have enabled the recommendation of dexamethasone in case of severe COVID-19 since mid-2020. Some societies recommended prescribing tocilizumab to pregnant patients with hypoxia and systemic inflammation from June 2021. Anti-SARS-CoV-2 monoclonal antibodies were authorized at the end of 2021 with conditional use in some countries, and then no longer recommended in Belgium and the USA at the end of 2022. The gradual convergence of the recommendations, although delayed compared to the general population, highlights the importance of the inclusion of pregnant women in clinical trials and of international collaboration to improve the pharmacological treatment of pregnant women with COVID-19.

Infant exposure to Fluvoxamine through placenta and human milk: a case series - A contribution from the ConcePTION project.

Introduction: Fluvoxamine is widely used to treat depression during pregnancy and lactation. However, limited data are available on its transfer to the fetus or in human milk. This case series provides additional information on the infant exposure to fluvoxamine during pregnancy and lactation. Case presentation: Two women, aged 38 and 34 years, diagnosed with depression were treated with 50 mg fluvoxamine during pregnancy and lactation. At delivery a paired maternal and cord blood sample was collected for each woman. The first mother exclusively breastfed her child for 4 months and gave one foremilk and one hindmilk sample at 2 days and 4 weeks post-partum, whereas the second mother did not breastfeed. Results: The cord to plasma concentration ratios were 0.62 and 0.48, respectively. At 2 weeks post-partum, relative infant doses (RID) were 0.47 and 0.57% based on fluvoxamine concentrations in foremilk and hindmilk, respectively. At 4 weeks post-partum, the RIDs were 0.35 and 0.90%, respectively. The child from the first mother was born healthy and showed a normal development at the 6th, 18th and 36th month follow-ups. One of the twins from the second woman was hospitalized for hypoglycemia that was attributed to gestational diabetes and low birth weight. The second one was born healthy. Conclusion: These results suggest a minimal exposure to fluvoxamine during lactation which is in accordance with previously published data. Larger clinical and pharmacokinetic studies assessing the long-term safety of this drug during lactation and the variability of its exposure through breastmilk are warranted.

Safety of medicines during breastfeeding - from case report to modeling: a contribution from the ConcePTION project.

INTRODUCTION: Despite many research efforts, current data on the safety of medicines during breastfeeding are either fragmented or lacking, resulting in restrictive labeling of most medicines. In the absence of pharmacoepidemiologic safety studies, risk estimation for breastfed infants is mainly derived from pharmacokinetic (PK) information on medicine. This manuscript provides a description and a comparison of the different methodological approaches that can yield reliable information on medicine transfer into human milk and the resulting infant exposure. AREA COVERED: Currently, most information on medicine transfer in human milk relies on case reports or traditional PK studies, which generate data that can hardly be generalized to the population. Some methodological approaches, such as population PK (popPK) and physiologically based PK (PBPK) modeling, can be used to provide a more complete characterization of infant medicine exposure through human milk and simulate the most extreme situations while decreasing the burden of sampling in breastfeeding women. EXPERT OPINION: PBPK and popPK modeling are promising approaches to fill the gap in knowledge of medicine safety in breastfeeding, as illustrated with our escitalopram example.

Impact of a primary care pharmacist consultations on pregnant women's medication use: the SafeStart intervention study linked to a national prescription database.

BACKGROUND: Prior studies show that pharmacist consultations are highly appreciated by pregnant women and feasible in community pharmacies. However, it is unknown whether such counseling has an impact on medication use during pregnancy. AIM: This study aimed to assess whether a pharmacist consultation in early pregnancy was associated with pregnant women's medication use, with a focus on antiemetic medications. METHOD: The SafeStart study recruited Norwegian pregnant women in the first trimester between February 2018 and February 2019. Women in the intervention group received a pharmacist consultation in a community pharmacy or by phone. A follow-up questionnaire was completed 13 weeks after enrollment. Data from the SafeStart study were linked to the Norwegian Prescription Database. Logistic regression was used to assess the association between the pharmacist intervention and medication use in the second trimester. RESULTS: The study included 103 women in the intervention group and 126 in the control group. Overall prescription fills in the first and second trimesters were 55% and 45% (intervention group) and 49% and 52% (control group), respectively. In total, 16-20% of women in the first trimester and 21-27% of women in the second trimester had a prescription for antiemetics. The pharmacist intervention was not associated with women's medication use in the second trimester. CONCLUSION: This study did not detect an impact of a pharmacist consultation on pregnant women's use of medications. In the future, pharmacist consultations should focus on other outcome factors, such as risk perception, knowledge level, and the use of other health care services. Trial registration The SafeStart study is registered with ClinicalTrials.gov (identifier: NCT04182750, registration date: December 2, 2019).

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.

Association of maternal personality traits with medication use during pregnancy to appraise unmeasured confounding in long-term pharmacoepidemiological safety studies.

Maternal personality is a possible confounder on the association between prenatal medication exposure and long-term developmental outcomes in offspring, but it is often unmeasured. This study aimed to (i) estimate the association between five maternal personality traits and prenatal use of acetaminophen (including extended use), opioid analgesics, antidepressants, benzodiazepines/z-hypnotics, and antipsychotics; (ii) evaluate, using an applied example, whether unmeasured confounding by maternal neuroticism would make the association between prenatal antidepressant-child ADHD null, using the E-value framework. We used data from 8,879 pregnant women and recent mothers who participated in the Multinational Medication Use in Pregnancy Study, a web-based cross-sectional study performed within the period from 1-Oct-2011 to 29-Feb-2012 in Europe, North America and Australia. Medication use in pregnancy was self-reported by the women. Personality was assessed with the Big Five Inventory, capturing the dimensions of neuroticism, extraversion, openness, agreeableness, and conscientiousness. Adjusted logistic regression analyses were conducted for each trait-medication pair, using the survey weighting. There was a strong association between having high neuroticism and prenatal use of antidepressants (Odds Ratio (OR): 5.63, 95% Confidence Interval (CI): 3.96-8.01), benzodiazepines/z-hypnotics (OR: 6.66, 95% CI: 4.05-10.95), and analgesic opioids (OR: 2.24, 95% CI: 1.41-3.56), but not with antipsychotics. Among women with mental illness, this association attenuated for benzodiazepines/z-hypnotics, but decreased to the null for antidepressants. High neuroticism (OR: 1.31, 95% CI: 1.08-1.59) and high openness (OR: 0.77, 95% CI: 0.64-0.93) were associated with extended use of acetaminophen. The E-value for the Hazard Ratio 1.93 in the applied example was 3.27. If the example study was conducted using a population comparison group, high maternal neuroticism could have explained away the association antidepressant-ADHD. Because the example study included only women with a mental illness, this risk of bias was assessed as minimal. Various personality dispositions in the mother are associated, with a different degree, to prenatal use of medication. The strength of these association can aid researchers in evaluating the influence of uncontrolled confounding by maternal personality in long-term safety studies in pregnancy, using the E-value. This assessment should always be performed in addition to a rigorous study design using approaches to triangulate the evidence.