Adverse Drug Reactions In Neonates Research Articles

Development and validation of a predictive tool for adverse drug reactions in neonates under intensive care.

Neonates hospitalized in neonatal intensive care units (NICUs) commonly experience adverse drug reactions (ADRs). Thus, we aimed to develop and validate a tool for predicting ADRs in neonates hospitalized in NICUs. A nested case-control study in an open cohort with neonates admitted to the NICU of a maternity hospital in Natal, Brazil was conducted from January 2019 to January 2022 [Correction added on 4 December 2023, after first online publication: 2023 has been changed to 2019 in the preceding sentence.]. Neonates with ADR were randomly paired with 2 controls. For the development of the tool, a multivariate logistic regression was applied on 2/3 of the sample (cases with respective controls). The model's fit was evaluated using the Hosmer-Lemeshow test for calibration and the Brier score for performance assessment. Validation of the tool was performed by determining the area under the receiver operating characteristic curve with bootstrap adjusted c-statistics. In all, 450 neonates (150 cases and 300 controls) were included in the study. We identified 5 independent risk factors for ADR, 4 related to the neonate (current mechanical ventilation, heart rate ≥178 beats/min, intravenous medications, ≥5 prescription medications) and 1 to the mother (gestational hypertension). The tool had a classification cut-off point of ≥15, and its total score ranged from 0 to 34. In validation, the tool had an area under the receiver operating characteristic curve of 0.74 (95% confidence interval [CI] 0.66-0.81) with sensitivity of 52.02% (95% CI 47.40-56.64) and specificity of 81.35% (95% CI 77.75-84.95). The tool demonstrated adequate discriminative ability and utilized 5 commonly monitored variables in the NICU.

Temporal profile of adverse drug reactions and associated clinical factors: a prospective observational study in a neonatal intensive care unit

ObjectiveAlthough adverse drug reactions (ADRs) are quite common in hospitalised neonates, pharmacovigilance activities in this public are still incipient. This study aims to characterise ADRs in neonates in a neonatal...

Adverse drug reactions in neonatal intensive care unit: Characteristics and risk factors

Adverse drug reactions (ADRs) in neonates can significantly affect expected clinical outcomes. The aim of this study was to analyze the prevalence and characteristics of ADRs and identify the risk factors involved in a neonatal intensive care unit (NICU). A prospective cohort study based on intensive pharmacovigilance was carried out in NICU of a public teaching hospital in the south of Mexico. Neonates admitted to the NICU who had between 1 and 90 days of age, with at least 24 hours of hospitalization, and a confirmed suspicion of ADRs were included. The prevalence and characteristics of ADRs were analyzed. Relative ratios (RR) were estimated with 95% confidence intervals (CI) to evaluate the risk factors of ADRs (p˂0.05). 998 newborns were included, 109 ADRs were detected in 75 newborns, the cumulative incidence was 7.51% and the ADRs were mainly probable imputability and moderate severity. The therapeutic group most frequently related to the development of ADRs was anti-infectives for systemic use and the blood and lymphatic system was most affected by the ADRs. Identified risk factors were: female sex (RR 1.58; 95% CI 1.01-2.47), prematurity (RR 5.6; 95% CI 3.45-9.11), low birth weight (RR 2.52; 95% CI 1.63-3.91), length of hospitalization >15 days (RR 12.95; 95% CI 7.89-21.25) and drugs administered >5 (RR 5.92; 95% CI 2.6-13.48). These results should be considered and studied in greater depth, which will allow the prevention of the development of ADRs in this group of patients.

Prospective identification and causality evaluation of suspected adverse drug reactions in neonates.

Neonates experience adverse drug reactions (ADRs), but under‐reporting of suspected ADRs to national spontaneous reporting schemes in this population is particularly high. A prospective observational study collected suspected neonatal ADRs at a tertiary neonatal unit. Cases were analysed for causality by six assessors using three existing methods. Sixty‐three suspected ADR cases were identified in 35/193 neonates (18.1%). The proportion of suspected ADRs where the drug was prescribed “off‐label” was 30/68 (44.1%). When 34 cases were assessed for causality using three methods, global kappa scores of less than 0.3 for each tool suggested only “fair” inter‐rater reliability. Neonatal ADRs can be captured and occur from a variety of drugs affecting many organ systems. The current tools for assessing causality need to be adapted before they can reliably assess neonatal ADRs.

O-24 Adrin 1 methodology study: adverse drug reactions in neonates: what are the best ways to evaluate suspected adverse drug reactions in neonates?

Background There are 90 000 babies admitted to neo-natal care units in the UK annually, and many of these require medications.1 Use of unlicensed and off-label medications is common in neonatal units, with accounting for up to 90% medicines.2 The incidence of adverse drug reactions (ADRs) in children is estimated to range between 0.6% and 16.8%, but the data specifically for neonates is limited.3 A number of tools exist to help clinicians to assess the causality of ADRs, but few have been validated in neonatal settings. This study aims to compare three existing methods for assessing causality of ADRs in a neonatal setting and to compare the outcomes be-tween tests and raters. Methods Following ethical approval, data were col-lected prospectively on suspected ADRs occurring in a tertiary neonatal care unit in the north of England over a five week period. Summaries of these cases were pre-sented to two investigators who undertook three sepa-rate causality assessments of each case using the Karch and Lasagna algorithm(KL), the Liverpool ADR Causality Assessment Tool (LCAT), and the New Adverse Drug Re-actions Algorithm for Infants in Neonatal Intensive Care Units(NAINICU).4,5,6 Inter-rater and inter-test statisti-cal analyses were performed. Results Causality assessments have been undertaken on 21 ADR cases reported from the unit to date. The KL algorithm rated 14.3% of cases as definite/likely, NAINICU 42.9% definite and LCAT 0% definite. Inter-rater reliability Kappa scores were 0.131, 0.136 and 0.294 for the 3 tools respectively. Inter-test reliability was greatest between the KL algorithm and the LCAT (Kappa 0.211) and least between NAINICU and LCAT (Kappa −0.149). Conclusion These three tools produced varied causali-ty assessment outcomes when used on neonatal ADRs. Marked inter-test and inter-rater variability was noted. The study is continuing to collect cases to help determine the optimal way to assess causaility in this popualtion.

PP-34 Adverse drug reactions in neonates: comparing retrospective spontaneous yellow card reports to prospectively collected reports

Background The UK Medicines and Healthcare prod-ucts Regulatory Agency (MHRA) encourages the report-ing of all adverse drug reactions (ADRs) in children that are ‘serious or result in harm’.1 The rate of under-report-ing of ADRs has been estimated to be approximately 94% and neonatal ADR reports are not influencing the clinical warnings issued by the MHRA.2,3 This study aims to compare reports of neonatal ADRs actively collected by a researcher from a tertiary neonatal unit to those reported to the UK yellow card system between 2001 and 2010. Methods An independent researcher collected data on ADRs in a tertiary neonatal care unit by daily ward round attendance, note reviewing and staff questioning. The results collected over four weeks were then compared to the yellow cards submitted to the MHRA between 2001 and 2010 by means of reviewing a recently published paper.3 Results Between 2001 and 2010 there were ninety seven yellow card reports of neonatal ADRs to the MHRA. Over a four week observational period thirty three neonatal ADR cases were suspected and reported by a researcher. The highest number of yellow card reports were for swine flu vaccinations (eight), whereas the researcher only collected one report relating to a vaccine, with the highest number of reports involving diuretics or antibiotics (six each). The yellow card reports most frequently reported rashes or erythema (twenty one) whereas the researcher most frequently reported electrolyte disturbances (seven), car-diac effects (five) or gastrointestinal effects (five). Conclusion There are a number of differences between neonatal ADRs reported to the MHRA and those occur-ring commonly. It is thought the predicted under-report-ing of ADRs and lack of knowledge or attention to neona-tal ADRs may be contributing to this.

[Adverse drug reactions in neonates hospitalized in neonatal intensive care units in Barranquilla, Colombia].

The appearance of adverse drug reactions in neonates is an important issue due to the lack of drug safety data. To identify the behavior of adverse drug reactions (ADR) in hospitalized neonates at two intensive care units in Barranquilla, Colombia. We conducted a cross-sectional prospective descriptive study based on patientcentered intensive pharmacosurveillance. We followed up and monitored the appearance of ADRs for six months. We used Naranjo's algorithm to assess causality, modified Hartwig and Siegel assessment scale to establish severity and Schumock and Thornton criteria to determine ADR preventability. We detected 123 adverse drug reactions in 78 neonates of the 284 monitored. The cumulative incidence of ADRs was 27.4% (78/284); incidence density was 30.60 ADRs per 1,000 patients/day (78/2,549). The most affected organ system was the digestive (33.6%). Systemic anti-infective drugs were the most involved pharmacological group. Most of the ADRs were mild (58.5%), 83% were classified as probable, 16.2% as possible and 0.8% as definite. ADR incidence was high in newborns, and it increased in preterm infants (less than 38 weeks of age).

Adverse drug reactions in neonates: a prospective study

AimTo investigate the frequency and characteristics of adverse drug reactions (ADRs) in hospitalised neonates to obtain a better understanding of and improvement in neonatal healthcare.MethodologyA prospective cohort study. Data were...

New Ways of Detecting ADRs in Neonates and Children.

Severe adverse drug reactions (ADRs) cause 5-7% of all hospital admissions, an estimated 2,000,000 severe reactions, and over 100,000 deaths each year in the USA. A recent systematic review indicated that the overall incidence of ADRs was 11% in hospitalized children and 1% in outpatients. Detecting ADRs in neonates and children is challenging, particularly because there are fewer clinical trials involving children than adults and drug use in children is common without a labeled indication. Ontogeny and significant physiological changes related to age have an impact on metabolic drug clearance and pharmacodynamics in children compared to adults, as well as on drug action. A variety of strategies have been developed for the identification and further evaluation of ADRs, starting from case reports and advancing into more structured methodologies, such as active surveillance, for accumulating the necessary information. While each approach has merit, a comprehensive surveillance approach with different methods is required to monitor drug safety in the post-market period. Among the methods that have shown value in neonates and children are anecdotal reporting, voluntary organized reporting, prescription event monitoring, pharmacoepidemiology using administrative databases, and active surveillance. There is an urgent need to improve the evaluation of paediatric drug safety in the pre- and post-market phases of drug evaluation in order to better predict in whom serious harm may occur and better ensure the safe use of drugs for neonates and children.

Adverse Drug Reaction in the Neonatal Intensive Care Unit: A Single Center Study

Purpose: Little research has been conducted on adverse drug reactions in neonates, particularly in Korea, where no studies have been reported. Methods: We conducted a retrospectively study using medical records in a neonatal intensive care unit from August 1, 2013 to July 31, 2014. The adverse drug reactions were evaluated according to the Naranjo algorithm, World Health OrganizationUppsala Monitoring Centre, and the Korean adverse drug reaction algorithm. Results: Of the 410 infants hospitalized during the study period, 57 cases of adverse drug reactions were reported in 40 infants (9.8%). The average gestational age was 28.4±4.3 weeks, the average birth weight was 1,184.1±622.0 g, and the adverse drug reactions were reported at an average of 21.0±29.7 days after birth. Causative agents were identified as electrolytes (36.8%), respiratory medication (14.0%), total parenteral nutrition (12.3%), lipid emulsion (10.5%), antibiotics (7.0%), non-steroidal antiinflammatory drugs (NSAIDs, 7.0%), sedatives (7.0%), vaccine (3.5%), and an antiviral medication (1.8%). Of the 57 cases, 55 (96.5%) cases demonstrated meaningful adverse drug reactions, defined as those given a score of “possible or above” in all 3 adverse drug reaction algorithms. Conclusion: More emphasis is warranted in the field of neonatal adverse drug reactions.

Adverse drug reactions in neonates and infants: a population-tailored approach is needed.

Drug therapy is a powerful tool to improve outcome, but there is an urgent need to improve pharmacotherapy in neonates through tailored prevention and management of adverse drug reactions (ADRs). At present, infants commonly receive off-label drugs, at dosages extrapolated from those in children or adults. Besides the lack of labelling, inappropriate formulations, (poly)pharmacy, immature organ function and multiple illnesses further raise the risk for ADRs in neonates and infants. Pharmacovigilance to improve the prevention and management of ADRs needs to be tailored to neonates and infants. We illustrate this using prevention strategies for drug prescription and administration errors (e.g. formulation, bedside manipulation, access), detection through laboratory signalling or clinical outlier data (e.g. reference laboratory values, overall high morbidity), assessment through algorithm scoring (e.g. Naranjo or population specific), as well as understanding of the developmental toxicology (e.g. covariates, developmental pharmacology) to avoid re-occurrence and for development of guidelines. Such tailored strategies need collaborative initiatives to combine the knowledge and expertise of different disciplines, but hold promise to become a very effective tool to improve pharmacotherapy and reduce ADRs in infants.

Clinical Application of Pharmacogenomics

The purpose of this review is to discuss the clinical application of pharmacogenomics for select drug therapies (eg, proton pump inhibitors [PPIs], codeine, and carbamazepine) and to highlight limitations and challenges that preclude implementation of pharmacogenomics into clinical practice. Genetic polymorphisms of cytochrome P450 (CYP) enzymes and the presence of the human leukocyte antigen (HLA)-B*1502 allele influence drug disposition and/or response. A portion of PPI pharmacokinetic and pharmacodynamic variability can be explained by CYP2C19 genotype. However, conflicting evidence exists related to Helicobacter pylori cure rates based on CYP2C19 genotype. For codeine, adverse drug reactions in neonates through breast-feeding from CYP2D6 ultra-rapid metabolizers have been reported. However, there is lack of conclusive evidence regarding the overall influence of CYP2D6 polymorphisms on codeine efficacy and toxicity. Although CYP2C19 and CYP2D6 genotyping tests are available, clinical utility remains low. The presence of the HLA-B*1502 allele is associated with carbamazepine-induced Stevens-Johnson syndrome (SJS) and/or toxic epidermal necrolysis (TEN). Pharmacogenomic testing is required prior to initiating carbamazepine in high-risk patients. Lack of sufficient resources, provider knowledge, and ethical, legal, and social issues are several limitations and challenges to implementing pharmacogenomic testing in clinical practice.

Intravenous Ceftriaxone and Calcium in the Neonate: Assessing the Risk for Cardiopulmonary Adverse Events

Unsolicited reports regarding potentially serious adverse drug reactions in neonates and young infants were reported to the Food and Drug Administration, leading to changes in the package label for ceftriaxone. This report describes and summarizes the reported cases that led to safety concerns regarding the concurrent administration of intravenous ceftriaxone and calcium in this age group. Nine reported cases were assessed. The Food and Drug Administration Adverse Event Reporting System database was searched for potential drug interactions in patients who were receiving concomitant ceftriaxone and calcium therapy. Eight of the reported 9 cases (7 were < or =2 months of age) represented possible or probable adverse drug events. There were 7 deaths. None of the cases were reported from the United States. The dosage of ceftriaxone that was administered to 4 of 6 infants for whom this information was available was between 150 and 200 mg/kg per day. The rate of occurrence of these serious adverse drug reactions cannot be accurately determined from available data. The concurrent use of intravenous ceftriaxone and calcium-containing solutions in the newborn and young infant may result in a life-threatening adverse drug reaction. Contributing factors for infants in this report may include the use of ceftriaxone at dosages higher than those approved by the Food and Drug Administration, intravenous "push" administration, and administration of the total daily dosage as a single infusion.

Analgesics and breast-feeding: safety considerations.

The issue of prescription of analgesics during lactation is clinically important but also complex. Most of the information available is based on single dose or short term studies, and for many drugs only a single or a few case reports have been published. As great methodological problems exist in the assessment of possible adverse drug reactions in neonates and infants, there is limited knowledge about the practical impact of the, often very low, concentrations found. Nevertheless, some recommendations can be made. Breast-feeding during maternal treatment with paracetamol (acetaminophen) should be regarded as being safe. Short term use of nonsteroidal anti-inflammatory drugs seems to be compatible with breast-feeding. For long term treatment, short-acting agents without active metabolites, such as ibuprofen, should possibly be preferred. The use of aspirin (acetylsalicylic acid) in single doses should not pose any significant risks to the suckling infant. Use of codeine is probably compatible with breast-feeding, although the effects of long term exposure have not been fully elucidated. For propoxyphene, it seems unlikely that the suckling infant will ingest amounts that will cause any detrimental effects during short term treatment. However, it cannot be excluded that significant amounts of the metabolite norpropoxyphene may arise in the suckling infant during long term exposure. Treatment of the mother with single doses of morphine or pethidine (meperidine) is not expected to cause any risk for the suckling infant. Repeated administration of pethidine, in contrast to morphine, affects the suckling infant negatively. Thus, morphine should be preferred in lactating mothers. However, during long term treatment with morphine, the importance of uninterrupted breast-feeding should be assessed on an individual basis against the potential risk of adverse drug effects in the infant. If it is decided to continue breast-feeding the infant should be observed for possible adverse effects. In general, if treatment of a lactating mother with an analgesic drug is considered necessary, the lowest effective maternal dose should be given. Moreover, infant exposure can be further reduced if breast-feeding is avoided at times of peak drug concentration in milk. As breast milk has considerable nutritional, immunological and other advantages over formula milk, the possible risks to the infant should always, and on an individual basis, be carefully weighed against the benefits of continuing breast-feeding.

Excretion of Psychotropic Drugs into Breast Milk

The prescription of psychotropic drugs during lactation is a clinically important but complex issue. Most of the information available on the excretion of these drugs into breast milk and the impact that this has on the breast-fed infant is based on single case reports. For many drugs, data are extremely sparse or even lacking. Although all psychotropic drugs that have been studied are excreted into breast milk, there is limited knowledge on the practical impact of the, often very low, concentrations found. On the other hand, the capacity for drug elimination is often impaired in infants compared with adults, indicating that even exposure to apparently insignificant doses through breast milk may cause adverse effects, particularly in premature neonates or after long term exposure. In addition, large methodological problems exist in the assessment of possible adverse drug reactions in neonates and infants. Nevertheless, based on current knowledge, some recommendations can be suggested.

Adverse Drug Reactions in Neonates

Adverse drug reactions (ADR) are uncommon causes of admission of neonates to the neonatal intensive care unit. The neonate, however, is potentially at significant risk for adverse drug reactions because of underdeveloped mechanisms and systems for handling drugs (the Gray Baby Syndrome with chloramphenicol as a classic example), the fact that infants in neonatal intensive care units are often critically ill with multiple organ system dysfunction, that they may be on multiple drugs, and that they may present with an adverse drug reaction as a result of exposure while still a fetus. There is also a history of misadventures in the neonatal intensive care unit and newborn nurseries due to exposure to antibacterial agents that produced systemic effects from percutaneous absorption. In this review, an overview of the mechanisms of adverse drug reactions will be presented, followed by a general review of the experience of adverse drug reactions in neonates and some specific examples of current adverse drug reactions and a suggested approach for the prevention and evaluation of adverse drug reactions in neonates.