Effective and safe pain relief in neonates matters. This is not only because of ethical constraints or human empathy, but even more because pain treatment is an important and crucial part of ...contemporary medical, paramedical, and nursing care to improve the outcome in neonatal intensive care graduates. Paracetamol (acetaminophen) is likely one of the pharmacological tools to attain this, with data on prescription practices suggesting that paracetamol is somehow the "rising star" in neonatal pain management. Besides very rare topical clinical scenarios like peripartal asphyxia and subsequent whole body hypothermia or the use of cardiorespiratory support devices, data on paracetamol pharmacokinetics and metabolism were reported throughout neonatal age or weight ranges, and we have summarized these data. In this review, we subsequently aimed to provide the reader with the currently available observations on the use of paracetamol as analgesic for different pain syndromes (major surgery, minor surgery or trauma, and procedural pain), with focus on the limitations of paracetamol when prescribed for neonatal procedural pain management. We hereby intentionally will not discuss other indications (patent ductus arteriosus and fever) for paracetamol administration in neonates. Based on the available evidence, paracetamol has opioid-sparing effects for major pain syndromes, is effective to treat minor to moderate pain syndromes, but fails for effective procedural pain management in neonates. This efficacy failure for procedural pain management should stimulate us to continue to search for more effective interventions, including non-pharmacological interventions and preventive strategies. Furthermore, there are also upcoming association type of epidemiological studies on the relation between exposure to analgesics-including paracetamol-and the negative short- or long-term outcome characteristics (neuro-behavioral, atopy, and fertility). Consequently and in addition to the search for effective alternatives to prevent or treat pain, studies on long-term outcome following paracetamol exposure are needed to inform all stakeholders on the full effect-side effect balance of the different strategies to treat pain.
Preterm infants are obviously born lighter and shorter, with smaller head circumferences than normal birth weight term born neonates. They also have a different body composition. Compromised growth ...is associated with adverse health outcomes. Both growth retardation and accelerated growth are suggested to cause metabolic, cardiovascular, and renal complications. Reviews regarding growth and body composition in preterm infants often do not differentiate between birth weight and gestational age. The purpose of this systematic review is to assemble growth data, specific in extremely low birth weight children. Different databases were searched for studies regarding growth and body composition in former extremely low birth weight infants until adulthood. We compared height, weight, head circumference, body mass index, fat mass, lean mass, fat distribution, and body water to matched normal birth weight controls and the World Health Organization growth charts. Studies consistently reported that former extremely low birth weight neonates experience a period of accelerated postnatal growth, but they achieve lower anthropometric parameters than normal birth weight children. There is no consensus about differences in body composition and how to measure this.
Conclusion
: Although extremely low birth weight infants exhibit a period of catch-up growth, their growth remains retarded later in life. Further research is needed to investigate body composition and the associated risk of cardiovascular diseases or metabolic syndrome.
What is Known:
• Extremely low birth weight infants have lower anthropometric parameters and a different body composition at birth and term-corrected age than normal birth weight infants.
• Former extremely low birth weight infants also have a higher risk on adverse cardiovascular health outcomes in later life.
What is New:
• After hospital discharge, extremely low birth weight neonates remain smaller and probably also lighter, with smaller head circumferences at each corrected age throughout childhood and adolescence when compared to normal birth weight infants or the World Health Organization growth charts. It is not clear whether extremely low birth weight infants reach a lower or similar body mass index score as normal birth weight infants.
• There is a lack of (long-term) information on body composition in extremely low birth weight infants.
A focused reflection on rational medicines use in neonates is valuable and relevant, because indicators to assess rational medicines use are difficult to apply to neonates. Polypharmacy and exposure ...to antibiotics are common, while dosing regimens or clinical guidelines are only rarely supported by robust evidence in neonates. This is at least in part due to the extensive variability in pharmacokinetics and subsequent effects of medicines in neonates. Medicines utilization research informs us on trends, on between unit variability and on the impact of guideline implementation. We illustrate these aspects using data on drugs for gastroesophageal reflux, analgesics or anti-epileptic drugs. Areas for additional research are drug-related exposure during breastfeeding (exposure prediction) and how to assess safety (tools to assess seriousness, causality, and severity tailored to neonates) since both efficacy and safety determine rational drug use. To further improve rational medicines use, we need more data and tools to assess efficacy and safety in neonates. Moreover, we should facilitate access to such data, and explore strategies for effective implementation. This is because prescription practices are not only rational decisions, but also have psychosocial aspects that may guide clinicians to irrational practices, in part influenced by the psychosocial characteristics of this population.
Abstract Paracetamol is commonly used to control mild-to-moderate pain or to reduce opioid exposure as part of multimodal analgesia, and is the only compound recommended to treat fever in neonates. ...Paracetamol clearance is lower in neonates than in children and adults. After metabolic conversion, paracetamol is subsequently eliminated by the renal route. The main metabolic conversions are conjugation with glucuronic acid and with sulphate. In the urine of neonates sulphated paracetamol concentration is higher than the glucuronidated paracetamol level, suggesting that sulfation prevails over glucuronidation in neonates. A loading dose of 20 mg/kg followed by 10 mg/kg every 6 hours of intravenous paracetamol is suggested to achieve a compartment concentration of 11 mg/L in late preterm and term neonates. Aiming for the same target concentration, oral doses are similar with rectal administration of 25 to 30 mg/kg/d in preterm neonates of 30 weeks’ gestation, 45 mg/kg/d in preterm infants of 34 weeks’ gestation, and 60 mg/kg/d in term neonates are suggested. The above-mentioned paracetamol doses for these indications (pain, fever) are well tolerated in neonates, but do not result in a significant increase in liver enzymes, and do not affect blood pressure and have limited effects on heart rate. In contrast, the higher doses suggested in extreme preterm neonates to induce closure of the patent ductus arteriosus have not yet been sufficiently evaluated regarding efficacy or safety. Moreover, focussed pharmacovigilance to explore the potential causal association between paracetamol exposure during perinatal life and infancy and subsequent atopy is warranted.
The extensive metabolic demands of pregnancy require specific physiological and anatomical changes. These changes affect almost all organ systems, including the cardiovascular, respiratory, renal, ...gastrointestinal, and hematologic system. The placenta adds another layer of complexity. These changes make it challenging for clinicians to understand presenting signs and symptoms, or to interpret laboratory and radiological tests. Furthermore, these physiological alterations can affect the pharmacokinetics and pharmacodynamics of drugs. Drug safety in lactation is only supported by limited evidence. In addition, the teratogenic effects of medications are often extrapolated from animals, which further adds uncertainties. Unfortunately, pregnant women are only rarely included in clinical drug trials, while doses, regimens, and side effects are often extrapolated from studies conducted in non-pregnant populations. In this comprehensive review, we present the changes occurring in each system with its effects on the pharmacokinetic variables. Understanding these physiological changes throughout normal pregnancy helps clinicians to optimize the health of pregnant women and their fetuses. Furthermore, the information on pregnancy-related physiology is also critical to guide study design in this vulnerable ‘orphan’ population, and provides a framework to explore pregnancy-related pathophysiology such as pre-eclampsia.
COVID-19 also affects pregnant and breastfeeding women. Hence, clinicians and policymakers require reliable evidence on COVID-19 epidemiology and consequences in this population. We aimed to assess ...the susceptibility of pregnant women to SARS-CoV-2 and women's perceived impact of the pandemic on their breastfeeding practices, medical counseling and social support. We performed a cross-sectional study using an online survey in primary care in Belgium. Pregnant and breastfeeding women and women who breastfed in the preceding four weeks were eligible to participate. The survey was distributed through social media in April 2020. In total, 6470 women participated (i.e., 2647 pregnant and 3823 breastfeeding women). Overall, 0.3% of all respondents reported to have tested positive for SARS-CoV-2, not indicating a higher susceptibility of pregnant women to contracting COVID-19. More than 90% refuted that the pandemic affected their breastfeeding practices, nor indicated that the coronavirus was responsible for breastfeeding cessation. Half of the women even considered giving longer breastmilk because of the coronavirus. In contrast, women's medical counseling and social support were negatively affected by the lockdown. Women without previous breastfeeding experience and in the early postpartum period experienced a higher burden in terms of reduced medical counseling and support. In the future, more consideration and alternative supportive measures such as tele-visits by midwives or perinatal organizations are required for these women.
The absorption of oral drugs is frequently plagued by significant variability with potentially serious therapeutic consequences. The source of variability can be traced back to interindividual ...variability in physiology, differences in special populations (age- and disease-dependent), drug and formulation properties, or food-drug interactions. Clinical evidence for the impact of some of these factors on drug pharmacokinetic variability is mounting: e.g. gastric pH and emptying time, small intestinal fluid properties, differences in pediatrics and the elderly, and surgical changes in gastrointestinal anatomy. However, the link of colonic factors variability (transit time, fluid composition, microbiome), sex differences (male vs. female) and gut-related diseases (chronic constipation, anorexia and cachexia) to drug absorption variability has not been firmly established yet. At the same time, a way to decrease oral drug pharmacokinetic variability is provided by the pharmaceutical industry: clinical evidence suggests that formulation approaches employed during drug development can decrease the variability in oral exposure. This review outlines the main drivers of oral drug exposure variability and potential approaches to overcome them, while highlighting existing knowledge gaps and guiding future studies in this area.
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Despite the increased use of medical cannabinoids, the efficacy and safety of the treatment among children remain uncertain. The objective was to study the efficacy and safety of medical cannabinoids ...in children. The search included studies through 11-May-2020. Selection criteria included studies evaluating efficacy and safety outcomes of medical cannabinoids (tetrahydrocannabinol, cannabidiol and other cannabis derivatives) versus control in children, independently assessed by two reviewers. Eight studies were included, all of which are randomized controlled trials. Cannabidiol is associated with 50% reduction in seizures rate (Relative Risk (RR) = 1.69, 95% CI 1.20-2.36) and caregiver global impression of change (Median Estimated difference = (- 1), 95%CI - 1.39-(- 0.60)) in Dravet syndrome, compared to placebo. While cannabidiol was associated with a reduction in reported seizure events (RR = 0.59, 95% CI 0.36-0.97), no association was found in products contained also tetrahydrocannabinol (RR = 1.35, 95% CI 0.46-4.03). Higher dose of cannabidiol was associated with decreased appetite (RR = 2.40, 95% CI 1.39-4.15). A qualitative assessment suggests that medical cannabinoids might be associated with adverse mental events. In conclusion, cannabidiol is associated with clinical improvement in Dravet syndrome. However, cannabidiol is also associated with decreased appetite. Adverse mental events were reported as well, however, more research should be performed to assess well this outcome.
Health-care professionals who prescribe medicines have the professional duty to choose medicines that are in the best interest of their individual patient, irrespective if that patient is an adult or ...a child. However, the availability of medicines with an appropriate label for pediatric use is lagging behind those for adults, and even available pediatric drugs are sometimes not suitable to administer to children. Consequently, health-care professionals often have no other option than to prescribe off-label medicines to children. An important reason for use of off-label medicines is to improve access to (innovative) treatments or to address medical needs and preferences of patients, especially when no other options are available. However, off-label use of medicines is in general not supported by the same level of evidence as medicines licensed for pediatric use. This may result in increased uncertainty on efficacy as well as the risk for toxicity and other side effects. In addition, liability may also be of concern, counterbalanced by professional guidelines.
Conclusion:
The purpose of this joint EAP/ESDPPP policy statement is to offer guidance for HCPs on when and how to prescribe off-label medicines to children and to provide recommendations for future European policy.
Background
Characterizing the dynamics of serum creatinine concentrations (Scr) and associated creatinine clearance (CLcr) as a measure of kidney function in extremely low birth weight (≤ 1000 g; ...ELBW) neonates remains challenging.
Methods
We performed a retrospective study that included longitudinal Scr (enzymatic assay) data from 148 ELBW neonates up to 6 weeks after birth. Change of Scr and inter-individual variability was characterized with nonlinear mixed-effect modeling. Key covariates such as gestational age (GA), mode of delivery (MOD), and treatment with ibuprofen or inotropic agents were investigated.
Results
A total of 2814 Scr concentrations were analyzed. GA was associated with Scr at birth (higher with advancing GA), and GA and MOD showed an association with postnatal maturation of CLcr (faster clearance increase with advancing GA and after C-section). Small CLcr decrease (≤ 5%) was quantified during ibuprofen treatment. For a GA of 27 weeks, mean Scr (estimated CLcr) at birth was 0.61 mg/dl (0.23 ml/min), increasing to 0.87 mg/dl (0.27 ml/min) at day three, and decreasing to 0.36 mg/dl (0.67 ml/min) at day 42 after birth.
Conclusions
We report the first mathematical model able to characterize Scr and CLcr in ELBW neonates during the first 6 weeks of life in a quantitative manner as a function of GA, MOD, and ibuprofen treatment. This model allows the derivation of GA-adjusted reference ranges for ELBW neonates and provides a rationale for normative Scr concentrations, and as such will help clinicians to further optimize monitoring and treatment decisions in this vulnerable patient population.
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