A core outcome set for pre‐eclampsia research: an international consensus development study

Objective To develop a core outcome set for pre‐eclampsia. Design Consensus development study. Setting International. Population Two hundred and eight‐one healthcare professionals, 41 researchers and 110 patients, representing 56 countries, participated. Methods Modified Delphi method and Modified Nominal Group Technique. Results A long‐list of 116 potential core outcomes was developed by combining the outcomes reported in 79 pre‐eclampsia trials with those derived from thematic analysis of 30 in‐depth interviews of women with lived experience of pre‐eclampsia. Forty‐seven consensus outcomes were identified from the Delphi process following which 14 maternal and eight offspring core outcomes were agreed at the consensus development meeting. Maternal core outcomes: death, eclampsia, stroke, cortical blindness, retinal detachment, pulmonary oedema, acute kidney injury, liver haematoma or rupture, abruption, postpartum haemorrhage, raised liver enzymes, low platelets, admission to intensive care required, and intubation and ventilation. Offspring core outcomes: stillbirth, gestational age at delivery, birthweight, small‐for‐gestational‐age, neonatal mortality, seizures, admission to neonatal unit required and respiratory support. Conclusions The core outcome set for pre‐eclampsia should underpin future randomised trials and systematic reviews. Such implementation should ensure that future research holds the necessary reach and relevance to inform clinical practice, enhance women's care and improve the outcomes of pregnant women and their babies

Integration of Pharmacogenetics and Pharmacogenomics in Drug Development: Implications for Regulatory and Medical Decision Making in Pediatric Diseases.

This article aims to provide an overview of the current situation regarding pharmacogenetic and pharmacogenomic (PG) studies in pediatrics, with a special focus on the role of PG data in the regulatory decision-making process. Despite the gap in pharmacogenetic research due to the lack of translational studies in adults and children, several technologies exist in drug development and biomarkers validation, which could supply valuable information concerning labeling and dosing recommendations. If performed under strict good clinical practice quality criteria, such findings could be included in the submission package of new chemical entities and used as additional information for prescribers, supporting further evaluation and understanding of the efficacy and safety profile of new medicines. Even though regulatory authorities may be aware of the potential role of PG in medical practice and guidances are available about the integration of PG in drug development, most data obtained from PG studies are not used by prescribers. The challenge is to better understand whether PG markers can be used to assess potential differences in drug response during the clinical program, so PG data can be integrated into the regulatory decision-making process, enabling the introduction of labeling information that promotes optimal dosing in the pediatric population

Morphine Glucuronidation in Preterm Neonates, Infants and Children Younger than 3 Years

Background and objective: A considerable amount of drug use in children is still unlicensed or off-label. In order to derive rational dosing schemes, the influence of aging on glucuronidation capacity in newborns, including preterms, infants and children under the age of 3 years was studied using morphine and its major metabolites as a model drug. Methods: A population pharmacokinetic model was developed with the nonlinear mixed-effects modelling software NONMEM (R) V, on the basis of 2159 concentrations of morphine and its glucuronides from 248 infants receiving intravenous morphine ranging in bodyweight from 500 g to 18 kg (median 2.8 kg). The model was internally validated using normalized prediction distribution errors. Results: Formation clearances of morphine to its glucuronides and elimination clearances of the glucuronides were found to be primarily influenced by bodyweight, which was parameterized using an allometric equation with an estimated exponential scaling factor of 1.44. Additionally, a postnatal age of less than 10 days was identified as a covariate for formation clearance to the glucuronides, independent of birthweight or postmenstrual age. Distribution volumes scaled linearly with bodyweight. Conclusions: Model-based simulations show that in newborns, including preterms, infants and children under the age of 3 years, a loading dose in mu g/kg and a maintenance dose expressed in mu g/kg(1.5)/h, with a 50% reduction of the maintenance dose in newborns younger than 10 days, results in a narrow range of morphine and metabolite serum concentrations throughout the studied age range. Future pharmacodynamic investigations are needed to reveal target concentrations in this population, after which final dosing recommendations can be made

Epileptic manifestations induced by midazolam in the neonatal period Manifestações epilépticas induzidas por midazolam no período neonatal

Antiepileptic drugs may cause worsening of epilepsy by aggravating pre-existing seizures or by triggering new seizure types. There are several reports of adverse effects related to midazolam, but only a few authors reported epileptic manifestations. We report four newborns seen at the Neonatal Intensive Care Unit of our University Hospital, who developed seizures a few seconds after the administration of midazolam. It is difficult to identify the patients at risk, but it is important to be aware and recognize this situation.<br>Drogas antiepilépticas podem piorar o controle da epilepsia por agravar crises epilépticas pre-existentes ou por desencadear novos tipos de crises. Existem vários relatos de eventos adversos relacionados ao midazolam; entretanto, poucos autores referem manifestações epilépticas. Neste estudo relatamos a ocorrência de crises epilépticas poucos segundos após a administração de midazolam, em quatro neonatos atendidos na Unidade de Terapia Intensiva do nosso hospital universitário. É difícil determinar quais pacientes estão em risco, mas é importante estar atento e reconhecer esta situação

Effect of multisensory stimulation on analgesia in term neonates: a randomized controlled trial

Many attempts have been made to obtain safe and effective analgesia in newborns. Oral glucose-water has been found to have analgesic properties in neonates. We investigated whether other sensory stimulation added to oral glucose provided more effective analgesia than oral glucose alone. In a randomized prospective double-blind trial, we studied 120 term newborns during heel prick. The babies were divided randomly into six groups of 20, and each group was treated with a different procedure during heel prick: A) control; B) 1 mL 33% oral glucose given 2 min before the heel prick; C) sucking; D) 1 mL 33% oral glucose plus sucking; E) multisensory stimulation including 1 mL 33% oral glucose (sensorial saturation); F) multisensory stimulation without oral glucose. Sensorial saturation consisted in massage, voice, eye contact, and perfume smelling during heel prick. Each heel prick was filmed and assigned a point score according to the Douleur Aiguë du Nouveau-né (DAN) neonatal acute pain scale. Camera recording began 30 s before the heel prick, so it was impossible for the scorers to distinguish procedure A (control) from B (glucose given 2 min before), C (sucking water) from D (sucking glucose), and E (multisensory stimulation and glucose) from F (multisensory stimulation and water) from the video. Procedure E (multisensory stimulation and glucose) was found to be the most effective procedure, and the analgesia was even more effective than that produced by procedure D (sucking glucose). We conclude that sensorial saturation is an effective analgesic technique that potentiates the analgesic effect of oral sugar. It can be used for minor painful procedures on newborn