Neonatal Adaptation Issues After Maternal Exposure to Prescription Drugs: Withdrawal Syndromes and Residual Pharmacological Effects

Exposure to drugs during pregnancy has the potential to harm offspring. Teratogenic effects are the most feared adverse outcomes in newborns; however, a wide spectrum of less known, usually reversible and often acute, neonatal adverse events can also occur due to drug intake by mothers during pregnancy, particularly in close proximity to delivery. This narrative review is aimed at the description of drugs and drug classes for which licit maternal use in the predelivery period has been associated with neonatal non-teratogenic disorders. For each drug class, epidemiology, clinical features, biological mechanism and management of these adverse reactions have been discussed in detail. Although these adverse reactions have been described mainly for substances used illicitly for recreational purposes, several prescription drugs have also been involved; these include mainly psychotropic medications such as opioids, antidepressants, antiepileptics and antipsychotics. These effects can be partly explained by withdrawal syndromes (defined also as 'neonatal abstinence syndrome') caused by the delivery-related discontinuation of the drug disposition from the mother to the fetus, with symptoms that may include feeding disorders, tremors, irritability, hypotonia/hypertonia, vomiting and persistent crying, occurring a few hours to 1 month after delivery. Otherwise, neonatal neurological and behavioral effects can also be caused by a residual pharmacological effect due to an accumulation of the drug in the blood and tissues of the newborn, with various symptoms related to the toxic effects of the specific drug class, usually developing a few hours after birth. With few exceptions, validated protocols for the assessment and management of withdrawal or residual pharmacological effects of these drugs in neonates are often lacking or incomplete. Spontaneous reporting of these adverse reactions seems limited, although it might represent a useful tool for improving our knowledge about drug-induced neonatal syndromes

Clinical differences among the elderly admitted to the emergency department for accidental or unexplained falls and syncope

It is difficult to distinguish unexplained falls (UFs) from accidental falls (AFs) or syncope in older people. This study was designed to compare patients referred to the emergency department (ED) for AFs, UFs or syncope. Data from a longitudinal study on adverse drug events diagnosed at the ED (ANCESTRAL-ED) in older people were analyzed in order to select cases of AF, syncope, or UF. A total of 724 patients (median age: 81.0 [65–105] years, 66.3% female) were consecutively admitted to the ED (403 AF, 210 syncope, and 111 UF). The number of psychotropic drugs was the only significant difference in patients with AF versus those with UF (odds ratio [OR] 1.44; 95% confidence interval 1.17–1.77). When comparing AF with syncope, female gender, musculoskeletal diseases, dementia, and systolic blood pressure >110 mmHg emerged as significantly associated with AF (OR 0.40 [0.27–0.58], 0.40 [0.24–0.68], 0.35 [0.14–0.82], and 0.31 [0.20–0.49], respectively), while valvulopathy and the number of antihypertensive drugs were significantly related to syncope (OR 2.51 [1.07–5.90] and 1.24 [1.07–1.44], respectively). Upon comparison of UF and syncope, the number of central nervous system drugs, female gender, musculoskeletal diseases, and SBP >110 mmHg were associated with UF (OR 0.65 [0.50–0.84], 0.52 [0.30–0.89], 0.40 [0.20–0.77], and 0.26 [0.13–0.55]), respectively. These results indicate specific differences, in terms of demographics, medical/pharmacological history, and vital signs, among older patients admitted to the ED for AF and syncope. UF was associated with higher use of psychotropic drugs than AF. Our findings could be helpful in supporting a proper diagnostic process when evaluating older patients after a fall

Evaluation of reporting risk for myopathy using the Italian National Network of Pharmacovigilance database: proton pump inhibitors and their interaction with statins

Muscular adverse reactions are well known adverse effects of statins. A weaker evidence exists also about the potential association between exposure to proton pump inhibitors (PPIs) and the development of myopathies. Current knowledge also rises the hypothesis that a treatment with PPIs might enhance the risk of developing drug-induced muscular injuries in patients receiving statins. This study was performed to detect the presence of signals of risk of muscular adverse reactions due to PPIs, either in the absence or in the presence of concomitant treatment with statins, in the Italian National Network of Pharmacovigilance (Rete Nazionale di Farmacovigilanza - RNF) database, managed by the Italian Drug Agency (Agenzia Italiana del Farmaco - AIFA). A case/non-case analysis was performed using spontaneous reports collected in the RNF database from July 1983 to May 2016. Cases were identified by reports containing at least one muscular adverse event (AE), using two different levels of specificity: myopathies and rhabdomyolysis. Non-cases were defined as all reports containing AEs other than muscular ones. Reports were divided in three index groups: 1) patients exposed to PPIs but not statins; 2) patients exposed to both PPIs and statins; 3) patients exposed to statins but not PPIs. The reference group consisted of patients using neither PPIs nor statins. For comparison of the index and reference groups, the reporting odds ratio (ROR) and 95% confidence intervals (CIs) were used as measure of reporting risk. In the primary analysis RORs were estimated to define the association between PPIs and muscular AEs, whereas in the secondary analysis the RORs for the reports of PPIs-statins combination were compared to those of statins, and the interaction was considered plausible when the ROR for the PPIs-statins group was numerically higher than the ROR reported for statins. The study was carried out on 274,104 reports. In the primary analysis, the RORs, adjusted for age and gender, of myopathy and rhabdomyolysis for PPIs were: 1.374 (95%CI: 1.208-1.563; p<0.001) and 1.667 (95%CI: 1.173-2.369; p<0.01), respectively. When RORs were adjusted for age, gender and thyroid dysfunction no substantial changes in point estimates and 95% CIs were observed. Considering the RORs adjusted for age, gender and number of drugs, a statistical significance was maintained for myopathies only (adjusted ROR: 1.487; 95%CI: 1.278-1.729; p<0.001). When specific PPIs were used as index groups, the RORs of rhabdomyolysis, adjusted for age and gender, resulted significant for lansoprazole (adjusted ROR: 2.050, 95%CI 1.140-3.688; p<0.05) and omeprazole (adjusted ROR: 2.142, 95%CI 1.244-3.690; p<0.01). In the secondary analysis, performed to compare the combination PPIs-statins with statins alone, RORs were not higher for any outcome of interest. The following combination where associated with a signal of potential interaction leading to rhabdomyolysis: esomeprazole-rosuvastatin and lansoprazole-rosuvastatin. This preliminary study suggests that the class of PPIs is involved in reports of muscular AEs, rather than any other AE, more frequently than any non-statin drug. When considering specific PPIs, only omeprazole and lansoprazole displayed a significant ROR for rhabdomyolysis. Concomitant treatments with PPIs and statins do not appear to increase further the RORs of muscular AEs associated with statins, with the exception of some specific combinations

Neuropsychiatric adverse events associated with statins: epidemiology, pathophysiology, prevention and management

Statins, or 3-hydroxy-3-methyl-glutaryl coenzyme A reductase inhibitors, such as lovastatin, atorvastatin, simvastatin, pravastatin, fluvastatin, rosuvastatin and pitavastatin, are cholesterol-lowering drugs used in clinical practice to prevent coronary heart disease. These drugs are generally well tolerated and have been rarely associated with severe adverse effects (e.g. rhabdomyolysis). Over the years, case series and data from national registries of spontaneous adverse drug reaction reports have demonstrated the occurrence of neuropsychiatric reactions associated with statin treatment. They include behavioural alterations (severe irritability, homicidal impulses, threats to others, road rage, depression and violence, paranoia, alienation, antisocial behaviour); cognitive and memory impairments; sleep disturbance (frequent awakenings, shorter sleep duration, early morning awakenings, nightmares, sleepwalking, night terrors); and sexual dysfunction (impotence and decreased libido). Studies designed to investigate specific neuropsychiatric endpoints have yielded conflicting results. Several mechanisms, mainly related to inhibition of cholesterol biosynthesis, have been proposed to explain the detrimental effects of statins on the central nervous system. Approaches to prevent and manage such adverse effects may include drug discontinuation and introduction of dietary restrictions; maintenance of statin treatment for some weeks with close patient monitoring; switching to a different statin; dose reduction; use of ω-3 fatty acids or coenzyme Q10 supplements; and treatment with psychotropic drugs. The available information suggests that neuropsychiatric effects associated with statins are rare events that likely occur in sensitive patients. Additional data are required, and further clinical studies are needed

Muscular Adverse Drug Reactions Associated with Proton Pump Inhibitors: A Disproportionality Analysis Using the Italian National Network of Pharmacovigilance Database

Introduction: Proton pump inhibitors (PPIs) have been implicated in the occurrence of moderate to severe myopathies in several case reports. Aim: This study was performed to assess the reporting risk of muscular adverse drug reactions (ADRs) associated with PPIs in the Italian National Network of Pharmacovigilance database. Methods: A disproportionality analysis (case/non-case) was performed using spontaneous reports collected in the database between July 1983 and May 2016. Reporting odds ratio (ROR) and 95% confidence intervals (CIs) were calculated as a measure of disproportionality. In a secondary and tertiary analysis, we explored the association of PPIs with muscular ADRs after taking into account the masking effect of statins. Moreover, the possibility of an interaction between PPIs and statins, leading to the occurrence of muscular ADRs, was also tested. Results: The study was carried out on 274,108 reports. The ROR of muscular ADRs for PPIs, adjusted for age and gender, was 1.484 (95% CI 1.204â\u80\u931.829; pÂ&nbsp

Allopurinol adherence among patients with gout: an Italian general practice database study

Allopurinol is used as long-term therapy to reduce the occurrence of gout flares. This study estimated the impact of patient adherence to allopurinol on hyperuricaemia (serum uric acid levels, sUA &gt;&nbsp;6&nbsp;mg/dl) and the identification of non-adherence predictors

Safety Profile of Certolizumab Pegol in Patients with Immune-Mediated Inflammatory Diseases: A Systematic Review and Meta-Analysis

INTRODUCTION: Certolizumab pegol (CZP), an anti-tumor necrosis factor PEGylated Fab' fragment of a humanized monoclonal antibody, is currently approved for treatment of some immune-mediated inflammatory diseases (IMIDs). To our knowledge, no systematic review and meta-analysis evaluating the overall safety profile of CZP has been performed. OBJECTIVE: The objective of this systematic review was to assess the adverse event (AE) patterns of CZP versus a control in patients with IMIDs. METHODS: A systematic literature search was performed using PubMed/MEDLINE, EMBASE, the Cochrane Library, and the FDA database for clinical trials up to March 2014. Eligible studies were those that compared the safety profile of CZP to a control group in patients with IMIDs. The following data were extracted: number of patients experiencing AEs, serious AEs (SAEs), adverse drug reactions (ADRs), withdrawals due to AEs, fatal AEs, infectious AEs and SAEs, upper respiratory tract infections, injection-site reactions, neoplasms, and tuberculosis. RESULTS: A total of 2023 references were identified and 18 randomized controlled trials were included. The main pooled risk ratios of CZP-treated versus control patients were as follows: AEs 1.09 (95% confidence interval, CI 1.04-1.14), SAEs 1.50 (95% CI 1.21-1.86), ADRs 1.20 (95% CI 1.03-1.39), infectious AEs 1.28 (95% CI 1.13-1.45), infectious SAEs 2.17 (95% CI 1.36-3.47), and upper respiratory tract infections 1.34 (95% CI 1.15-1.57). CONCLUSION: Safety data on CZP suggest an overall favorable tolerability profile, with infections being the most common AE. However, CZP-treated patients had a twofold higher risk of infectious SAEs than control patients. Large observational studies and data from national registries are needed to detect rare AEs, which might occur after long-term exposures to CZP

Quality of adverse drug reaction (QADRA) reports: an algorithm to appraise the efficiency of spontaneous reporting systems in pharmacovigilance

Aim: To design and validate an algorithm for the multidimensional evaluation of the quality of adverse drug reaction (ADR) case reports (QADRA). Subject and methods: One hundred fifty-three patients randomly and retrospectively selected from 15,906 records included in the Italian database of spontaneous ADR reports throughout 2009. Each report was evaluated by two panels of experts blinded to one another as well as by the algorithm developed in the present study. Each case was classified taking three parameters into consideration: plausibility, notoriety and clinical relevance. Results: The two panels assessed that 21.6 % of reports were of "high" quality. When applying the QADRA algorithm (score range 0-15), its median value was 6 (4-7, 25 and 75 percentiles, respectively). The area under the receiver operator characteristics (ROC) curve, which assesses the ability of the risk score to predict the report quality, was 0.93 (95 % CI: 0.88-0.97). Herein, the cut-off points ≤5, 6 or 7 and ≥8 indicated the best balance between sensitivity and specificity, and they could be used to categorize the reports as being of 'high', 'intermediate' and 'low' quality (AUC = 0.87; 95 % CI: 0.80-0.92), respectively. Conclusion: The QADRA algorithm performs as a reliable and complete tool for assessing the quality of ADR reports. Several potential applications of this algorithm should be investigated in the future, both for scientific purposes and healthcare system management. © 2013 Springer-Verlag Berlin Heidelberg