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Background: Young children's healthy development depends on nurturing care, which ensures health, nutrition, responsive caregiving, safety and security, and early learning. Infancy and childhood are characterized by rapid growth and development, and these two factors contribute largely to determining health status and well-being across the lifespan. Identification of modifiable risk factors and prognostic factors during the critical periods of life will contribute to the development of effective prevention and intervention strategies. The NASCITA (NAscere e creSCere in ITAlia) study was created to evaluate physical, cognitive, and psychological development, health status and health resource utilization during the first six years of life in a cohort of newborns, and to evaluate potential associated factors., Methods: NASCITA is an ongoing, dynamic, prospective, population-based birth cohort study of an expected number of more than 5000 newborns who will be recruited in 22 national geographic clusters starting in 2019. It was designed to follow children from birth to school entry age for a wide range of determinants, disorders, and diseases. Recruitment of the newborns (and their parents) will take place during the first routine well-child visit, which takes place at the office of the pediatrician assigned to them by the local health unit of residence, and which is scheduled for all newborns born in Italy within the first 45 days of their life. Data will be web-based and collected by the family pediatricians during each of the 7 standard well-child visits scheduled for all children during their first 6 years of life. Information on every contact with the enrolled children in addition to these prescheduled visits will be also recorded., Discussion: The NASCITA cohort study provides a framework in which children are followed from birth to six-years of age. NASCITA will broaden our understanding of the contribution of early-life factors to infant and child health and development. NASCITA provides opportunities to initiate new studies, also experimental ones, in parts of the cohort, and will contribute relevant information on determinants and health outcomes to policy and decision makers. Cohort details can be found on https://coortenascita.marionegri.it., Trial Registration: Clinicaltrials.gov: NCT03894566. Ethics committee approval: 6 February 2019, Verbale N 59.

Background: Clinical trial registries have been a priority topic in the past few years in promoting data transparency and accountability. In this context, in 2011, the IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri" set up a registry to collect data on all studies in which the institute's researchers are involved. In this study we present a self-audit in order to detect the lead researchers' general knowledge on registries, the completeness and quality of the randomized controlled trial (RCT) data inputted in an Italian research institute's registry, and the researchers' adherence to both registration requirements and the institute transparency goal, aiming to improve standards and leading to greater awareness of the issues involved., Methods: A questionnaire-based audit was conducted. To interview researchers we included questions ranging from general knowledge on registries (e.g., what are the aims of registries?) to questions about their knowledge of the Mario Negri's registry, questions on selected trials and registration, included information on the protocol, and the results., Results: The audit sample covers 12 of the 47 RCTs at the institute's Milan branch, representing all the possible lead researchers responsible for RCTs at the institute. The researchers have more than a basic knowledge of trial registries and their aims. All the researchers reported that they know of the ClinicalTrials.gov registry and most of them reported that they frequently use it; however, only a few know about the World Health Organization's registry platform (International Clinical Trials Registry Platform). The most cited registry aims reported were increased transparency and reduced publication bias. Of the studies registered in the institute's registry, 92% had at least one data item missing in the registry record. Concerning trial registration in the international registries, all 12 respondents said their trial had been registered and specified the registry name, but often they had not inputted the associated trial ID code in the corresponding field of the institute's registry. Concerning two important issues on data transparency and ethical standards, namely registration timing and result reporting, 11 stated that their trial was registered before starting recruitment, and for five of six closed trials they stated that their results have been already published-for one trial within 1 year after its completion., Conclusions: Researchers should guarantee correct reporting of trials and their data as a rule of great ethical value. Institutional self-audits should be performed periodically in order to improve clinical trial disclosure.

Clinical trial registries are being increasingly acknowledged worldwide. We searched for possibly trustworthy online registries that are not already included in the International Clinical Trials Registry Platform to evaluate whether other useful trial data sources exist and whether they could potentially be consulted, since the strategy search within this platform has recently been questioned. Fifty-nine registries were initially identified, and 11 of them fit the criteria applied and were analyzed for quality and usability. Four additional, potentially reliable registries were identified that researchers could exploit in order to obtain a more global view of the issue being investigated.

Purpose: Quality of care is strongly influenced by evidence-based medicine, a large part of which is based on results obtained from clinical trials. If trials are conducted in secret, patient safety is at risk. Several mandates-legal, editorial, financial, and ethical-have tried to influence the disclosure of clinical trials, first by encouraging registration in publicly accessible registers and, second, by calling for the publication of results. Not all these initiatives have reached high rates of compliance, but the succession of national and international events over a few years gave an important boost to information disclosure. This article provides a chronicle of the succession of the events, from the historical calls to the recent EMA policy and WHO statement, and public consultations requested by the NIH, and the HHS, which will inevitably change the international panorama. The path of these new policies is moving towards more supervised clinical research. Individual scientific institutions can also contribute, at the local level, to such an ethical endeavor as is improving research transparency, by disclosing information on the trials coordinated by their own researchers., Results: The way is long and complex, but, if everyone contributes there could be a prompt, worldwide diffusion of the findings of clinical trials, and therefore a more possible evidenced-based medicine.

Background: Tuberculosis (TB) during pregnancy may lead to severe consequences affecting both mother and child. Prenatal care could be a very good opportunity for TB care, especially for women who have limited access to health services. The aim of this review was to gather and evaluate studies on TB care for pregnant women., Methods: We used a combination of the terms "tuberculosis" and "pregnancy", limited to human, to search for published articles. Studies reflecting original data and focusing on TB care for pregnant women were included. All references retrieved were collected using the Reference Manager software (Version 11)., Results: Thirty five studies were selected for review and their data showed that diagnosis was often delayed because TB symptoms during pregnancy were not typical. TB prophylaxis and anti-TB therapy appeared to be safe and effective for pregnant women and their babies when suitable follow up and early initiation were present, but the compliance rate to TB prophylaxis is still low due to lack of follow up and referral services. TB care practices in the reviewed studies were in line in principle with the WHO International Standards for Tuberculosis Care (ISTC)., Conclusions: Integration of TB care within prenatal care would improve TB diagnosis and treatment for pregnant women. To improve the quality of TB care, it is necessary to develop national level guidelines based on the ISTC with detailed guidelines for pregnant women.

A survey was set up to gauge the opinions of neonatologists on the role of Ureaplasma in bronchopulmonary dysplasia (BPD) development, the use of azithromycin for BPD prevention, and the factors influencing azithromycin use in European neonatal intensive care units (NICUs). 167 NICUs participated in the survey, representing 28 European countries. For respondents, the two major perceived risk factors for BPD were prematurity of <28 weeks and high oxygen requirements. Only 38% of NICUs had a protocol for BPD prevention and 47% routinely tested for Ureaplasma. In cases of infection, macrolides were the first choice. Most (78%) NICUs were interested in participating in a trial evaluating azithromycin safety and efficacy in reducing BPD rates. Opinions and clinical practice varied between European neonatal units, and differences in Ureaplasma treatment and prevention of BPD highlight the need for further azithromycin evaluation and for improved therapeutic knowledge in preterms.

Objective: Clinical trials registries are important for guaranteeing trustworthy scientific knowledge. Despite international initiatives promoting trial registration, however, complete and high quality disclosure of trial information in such registries is not routine. The role of registries in also increasing transparency is fundamental, and these databases could be contemplated by research organizations, even at more local levels., Methods: A rare initiative was set up at the IRCCS-Mario Negri Institute for Pharmacological Research in Milan in order to make the institute's ongoing research accessible to anyone., Results: The register currently includes 112 studies in which the institute participates., Conclusions: Work still needs to be done to improve the registry, but it is up and functional. Could, or should, such registries be routine for all scientific institutions?

Purpose: To describe the use of ciprofloxacin and fluconazole for the treatment of sepsis in European neonatal intensive care units (NICUs) in order to better orient research aimed at acquiring essential knowledge in this critical area., Methods: The survey consisted of an online questionnaire for all participating NICUs on treatment schemes employed, rationales behind drug choices and interest in participation in research involving the two drugs., Results: A total of 189 level II and III NICUs participated in the survey, representing 25 countries, with Italy, UK and France providing the greatest number of centres (54 % of total). Ciprofloxacin is used in 25 % of NICUs that responded, although the indications for administering it vary between centres and the dosage ranges vary considerably, with 25 % of NICUs giving ≤10 mg/kg/day and another 25 % giving ≥21 mg/kg/day. Factors given as affecting the decision to use ciprofloxacin are uncertainty about its safety and pharmacokinetics and level of penetration in the cerebrospinal fluid. Among the 70 % of responding units that use fluconazole to treat fungal infection, 45 % administer 6 mg/kg unit doses while 33 % administer 12 mg/kg; 41 % of NICUs use a 24-h interval between administrations while 20 % wait 72 h. Among the responding NICUs, 57 % were willing to participate in a project on ciprofloxacin and 59 % would consider participating in a randomized controlled trial evaluating fluconazole versus micafungin., Conclusions: Great variability in therapies exists within and between countries. Numerous centres are interested in participating in research on these drugs, highlighting the need for further knowledge on sepsis treatment and European centres' interest in off-patent medicine research.

Unlabelled: Neonatal fungal infections are associated with substantial mortality and morbidity. Although prophylactic use of several antifungals has been proposed, this practice remains controversial. In order to evaluate the use of fluconazole prophylaxis in European NICUs, we conducted a cross-sectional survey by means of a structured questionnaire that was sent to European level II and III neonatal intensive care units, over a 9-month period, as part of a neonatal research FP7 European project. A total of 193 questionnaires from 28 countries were analysed. Use of antifungal prophylaxis was reported by 55% of the responders, and the most frequently used antifungal agent was fluconazole (92%). Main indications for prophylaxis were low gestational age (<28 weeks) and birth weight (<1,000 g). A dose of 3 mg/kg was used in 66% of NICUs using fluconazole, with an administration interval of 72 h in 52% of them. All responders acknowledged the need for additional trials on the efficacy of prophylactic fluconazole. Non-users of fluconazole prophylaxis were more likely to be influenced by the local incidence of candidiasis, the risk of increasing antifungal resistance and the absence of specific recommendations by paediatric societies., Conclusions: Major concerns about the use of fluconazole prophylaxis include its efficacy, the risk of emergence of resistant species and the absence of clear consensus to support routine use. Future studies that address these issues will contribute to a more rational use of fluconazole prophylaxis.

Given the increased attention on cystic fibrosis care during the last few years in Italy, this study was performed to evaluate content quality, characteristics and completeness of Italian cystic fibrosis websites. GOOGLE was used and retrieved websites were evaluated for the presence of predefined descriptive criteria and disease information. Their contents were compared with available evidence. Thirty sites were evaluated. Few fulfilled the criteria, such as listing authors (24 sites) and citing references (10). The amount of disease information varied, but 23 provided treatment information. Of these, 11 comparable sites were evaluated for adherence to guidelines and overall completeness. All information adhered to guidelines. One site provided very thorough information and was the most complete, whereas four were found to be half as complete as others. Patients can find accurate cystic fibrosis knowledge online, but may need to navigate between multiple sites to obtain comprehensive coverage of disease information. In Italy, a network of association websites exists to support patients and families. Website quality could be improved in terms of documentation (transparency) of the information provided in order to permit users to select well-documented, updated information.

Objective: To describe the results and conclusions of DEC-net, an international, publicly available register of paediatric drug therapy clinical trials, and to assess which paediatric health areas are covered by research and by which trial types., Methods: The contents of the register, which was set up by four groups (Italy, UK, France, Spain) who searched for paediatric trials and collected data between 2004-2006, were analysed. The disease areas reflected were compared with those covered by published trials and Burden of Disease (BD) data., Results: In all, 257 trial records were analysed, 86 of which were entered by the Italian partner, 84 by the UK partner, 56 by the French partner and 31 by the Spanish partner. Spain entered the majority of multinational trials, while the UK had the majority of single-centre national trials. Most trials were experimental (79%), and the most commonly represented diseases were neoplasms (14% trials). In all, 28% were double-blind randomised controlled trials (RCTs). The most common disease areas addressed in the 257 trials were similar to the published trials' areas. In contrast, the primary research area was low on the BD list., Conclusions: DEC-net has demonstrated that international research efforts exist, even for paediatrics, although there may be an imbalance between national and multinational studies and a limited approach to double-blind RCTs. Recent initiatives will increase the number of children participating in research, and European legislation will require prospective registration. Paediatric research priorities must be better defined, however, and this can be done by registering research and making the information available to all relevant actors.

Clinical trials have a fundamental role in promoting an evidence based use of drugs in adults and in children. However, it is often difficult to identify the few paediatric studies carried out and to thus implement knowledge derived from them. Furthermore, studies that are stopped prematurely or that have insignificant or negative results often remain unpublished, leading to duplication of effort by researchers, waste of resources and concealment of potentially toxic risks. The European Community decided to support the development of a European register of clinical trials in children as part of the Fifth Framework Thematic Programme "Quality of Life" in 2002. The project DEC-net is coordinated by the Laboratory of Mother and Child Health of the Mario Negri Institute for Pharmaceutical Research in Milan and currently involves members of four countries; France, Italy, Spain and the United Kingdom. It is unique in that it is the first population oriented clinical trial register. Such a register represents a useful source for planning new studies, promoting communications and collaborations between researchers, facilitating patient access and recruitment into trials, preventing trial duplication and inappropriate funding and identifying the therapeutic needs of children that remain neglected. It will also allow for active monitoring of new or evolved knowledge of drug therapies.

Background: The need to register a clinical trial in a public database has been widely discussed in the last few years. Several general clinical trial registers have been developed, but none are dedicated to children. A web-based register of trials on drug therapy in children was therefore developed., Purpose: The general objective of the project, called DEC-NET (European register of clinical trials on medicines for children - drug evaluation in children) and supported by the European Community, is to provide the scientific community with a flexible tool for promoting communication and collaboration among researchers, disseminating clinical trial results and facilitating patient access and recruitment to trials., Methods: We identified a set of trial data to be collected, including general trial information, recruitment information, eligibility criteria, clinical trial characteristics, location and contact information, study drugs, study sponsor and results. The system was set up to allow authorized users (working in Italy, Spain, France and UK) to enter, handle and monitor the trial information. Medical data dictionaries (ie, ICD-9 and ATC) were used in order to make the data-entry and the search and data analysis procedures easier. A multilingual approach in data handling and presentation made accessing trial information in English and in the language of the country where the study is located feasible. Search and browsing tools were set up to allow investigators, researchers, and citizens to freely search and browse the entire register and access the details of trials meeting the search criteria., Results: The DEC-net register (http://www.dec-net.org) was opened for trial notification and consultation., Limitations: DEC-net currently involves four European countries and is a pilot project., Conclusions: It is hoped that what has been achieved so far represents only the beginning of a long-term project, and the next step will be to extend the register's use to other European countries.

Unlabelled: The aim was to compare results of studies performed in different settings worldwide and identify common therapeutic areas to allow for focused interventions, because off-label drug use can be a measure of the lack of knowledge concerning paediatric treatments. A secondary objective was to provide a brief review of efforts to date. A literature review of articles on off-label and unlicensed drug use in children involving general prescription samples was performed using Medline and Embase. In all, 30 studies from 1985-2004 were included. Eleven involved paediatric hospital wards, seven neonatal hospital wards, and 12 the community setting. The off-label and unlicensed classification methods varied, making results difficult to compare. In general, off-label/unlicensed prescription rates ranged from 11%-80%, and higher rates were found in younger versus older patients and in the hospital versus community settings. On the paediatric hospital wards, off-label/unlicensed prescriptions ranged from 16%-62% and most often concerned acetaminophen, cisapride, chloral hydrate, and salbutamol. In the neonatal wards, rates ranged from 55%-80% and often involved caffeine. In the community setting, rates ranged from 11%-37% and the most commonly implicated drugs were salbutamol and amoxicillin., Conclusion: A lack of harmonization between the evidence, the information available to doctors, and its use in clinical practice exists and this is part of the reason off-label therapies are so common. Attempts have been made to improve knowledge concerning paediatric treatments, but more focused interventions are needed, also taking into consideration this lack of harmonization.

Aim: To evaluate the reason off-label use exists in paediatric general practice and to distinguish between non-compliance with respect to regulatory standards and non-compliance with respect to guidelines in order to determine what this difference means in terms of rational prescribing., Methods: Information on patients visited by 35 general paediatricians in southern Italy was collected and their prescriptions analysed for off-label status. Off-label drug use in the Italian paediatric community setting was assessed. A sample indication, pharyngotonsillitis, was chosen and the related prescriptions analysed, distinguishing between non-compliance with regulatory standards (i.e. off-label use) and non-compliance with guidelines, in order to determine the appropriateness of prescribing., Results: Information was collected on 9917 patients (8476 prescriptions). In all, 17% of prescriptions were off label. When the 1675 pharyngotonsillitis prescriptions were analysed, 8% were off label and 63% were not in accordance with the guidelines. On the other hand, 55% of these prescriptions did not adhere to the guidelines, but were not off label either., Conclusion: The results of this study were surprising because off-label drug use for pharyngotonsillitis, a common paediatric condition, was low, while non-adherence to guidelines was high. In cases such as this one, in which guidelines exist, physicians' prescribing habits were irrational because they did not follow the evidence. Physicians should keep up to date with new knowledge and should be provided with updated product information.

Aims: To explore the usefulness of data derived from observational studies on adverse drug reactions (ADRs) in defining and preventing the risk of pharmacological interventions in children in different health care settings., Methods: A systematic review of studies on ADRs in hospitalized children, in outpatient children, and on ADRs causing paediatric hospital admissions was performed. Studies were identified through a search of the MEDLINE and EMBASE databases. The inclusion criteria required that the population was not selected for particular conditions or drug exposure and prospective monitoring was used for identifying ADRs. Data were analysed by a random-effects model., Results: Seventeen prospective studies were included. In hospitalized children, the overall incidence of ADRs was 9.53% (95% confidence interval [CI], 6.81, 12.26); severe reactions accounted for 12.29% (95%CI, 8.43,16.17) of the total. The overall rate of paediatric hospital admissions due to ADRs was 2.09% (95%CI, 1.02, 3.77); 39.3% (95%CI, 30.7,47.9) of the ADRs causing hospital admissions were life threatening reactions. For outpatient children the overall incidence of ADRs was 1.46% (95%CI, 0.7, 3.03)., Conclusions: The results show that ADRs in children are a significant public health issue. The completeness and accuracy of prescription reporting as well as clinical information from studies was a rarity, making it difficult for health practitioners to implement evidence based preventive strategies. Further, methodologically sound drug surveillance studies are necessary for an effective promotion of a safer use of drugs in children.

Background: We examined how maternal socio-demographic factors, together with mother's education, knowledge, and perception of immunizations, can affect the uptake of optional vaccinations of preschool children in Italy., Methods: Interviews of Italian mothers were performed using a structured questionnaire administered by trained interviewers with no specific medical competence., Results: A convenience sample of 1,035 mothers were interviewed. Fifty-nine percent of the respondents reported to have had their child immunized with the MMR vaccine and 54% reported to have had their child immunized against pertussis. In logistic regression analysis, three variables were significantly associated with both the immunization outcomes: mother's positive attitude toward immunization (OR = 1.69; IC 1.13-2.52 for pertussis; OR = 1.86, IC 1. 17-2.96 for MMR); mothers' residency in the North of the country (OR = 1.74; IC 1.32-2.30 for pertussis; OR = 1.63, IC 1.18-2.24 for MMR); and mother's receipt of satisfactory information on immunization (OR = 1.67; IC 1.15-2.21 for pertussis; OR = 2.25, IC 1. 47-3.43 for MMR). An immunization performed in recent years (after 1994), probably following the widespread use of acellular vaccine, was the most significant predictor for pertussis immunization (OR = 3.21; IC 2.43-4.24)., Conclusions: The findings suggest that mothers' attitudes, educational level, and socio-demographic characteristics, as well as socio-economic factors and local health policies, can influence children's immunization uptake. Health promotion, based on a partnership between parents and health professionals, should become a priority in Italian vaccination policies., (Copyright 2000 American Health Foundation and Academic Press.)

Objective: To determine the extent of use of unlicensed and off label drugs in children in hospital in five European countries., Design: Prospective study of drugs administered to children in general paediatric medical wards over four weeks., Setting: Children's wards in five hospitals (one each in the United Kingdom, Sweden, Germany, Italy, and the Netherlands)., Subjects: Children aged 4 days to 16 years admitted to general paediatric medical wards., Main Outcome Measure: Proportion of drugs that were used in an unlicensed or off label manner., Results: 2262 drug prescriptions were administered to 624 children in the five hospitals. Almost half of all drug prescriptions (1036; 46%) were either unlicensed or off label. Of these 1036, 872 were off label and 164 were unlicensed. Over half of the patients (421; 67%) received an unlicensed or off label drug prescription., Conclusions: Use of off label or unlicensed drugs to treat children is widespread. This problem is likely to affect children throughout Europe and requires European action.

Background: Health information on the Internet, with respect to common, self-limited childhood illnesses, has been found to be unreliable. Therefore, parents navigating on the Internet risk finding advice that is incomplete or, more importantly, not evidence-based. The importance that a resource such as the Internet as a source of quality health information for consumers should, however, be taken into consideration. For this reason, studies need to be performed regarding the quality of material provided. Various strategies have been proposed that would allow parents to distinguish trustworthy web documents from unreliable ones. One of these strategies is the use of a checklist for the appraisal of web pages based on their technical aspects., Objective: The purpose of this study was to assess the quality of information present on the Internet regarding the home management of cough in children and to examine the applicability of a checklist strategy that would allow consumers to select more trustworthy web pages., Methods: The Internet was searched for web pages regarding the home treatment of cough in children with the use of different search engines. Medline and the Cochrane database were searched for available evidence concerning the management of cough in children. Three checklists were created to assess different aspects of the web documents. The first checklist was designed to allow for a technical appraisal of the web pages and was based on components such as the name of the author and references used. The second was constructed to examine the completeness of the health information contained in the documents, such as causes and mechanism of cough, and pharmacological and nonpharmacological treatment. The third checklist assessed the quality of the information by measuring it against a gold standard document. This document was created by combining the policy statement issued by the American Academy of Pediatrics regarding the pharmacological treatment of cough in children with the guide of the World Health Organization on drugs for children. For each checklist, the web page contents were analyzed and quantitative measurements were assigned., Results: Of the 19 web pages identified, 9 explained the purpose and/or mechanism of cough and 14 the causes. The most frequently mentioned pharmacological treatments were single-ingredient suppressant preparations, followed by single-ingredient expectorants. Dextromethorphan was the most commonly referred to suppressant and guaifenesin the most common expectorant. No documents discouraged the use of suppressants, although 4 of the 10 web documents that addressed expectorants discouraged their use. Sixteen web pages addressed nonpharmacological treatment, 14 of which suggested exposure to a humid environment and/or extra fluid. In most cases, the criteria in the technical appraisal checklist were not present in the web documents; moreover, 2 web pages did not provide any of the items. Regarding content completeness, 3 web pages satisfied all the requirements considered in the checklist and 2 documents did not meet any of the criteria. Of the 3 web pages that scored highest in technical aspect, 2 also supplied complete information. No relationship was found, however, between the technical aspect and the content completeness. Concerning the quality of the health information supplied, 10 pages received a negative score because they contained more incorrect than correct information, and 1 web page received a high score. This document was 1 of the 2 that also scored high in technical aspect and content completeness. No relationship was found, however, among quality of information, technical aspect, and content completeness., Conclusions: As the results of this study show, a parent navigating the Internet for information on the home management of cough in children will no doubt find incorrect advice among the search results. (ABSTRACT TRUNCATED)

Background: We examined mothers' knowledge of, attitudes toward, and management of fever in their children., Methods: Interviews of mothers of preschool children were performed using a structured questionnaire administered by interviewers with no specific medical competence., Results: Of a total of 1,237 mothers who were interviewed, data were analyzed for the 707 mothers who had coped with a febrile episode in their children during the previous month. Of these, 59% were concerned about fever in their children and 17% were very worried. At the onset of fever, 48% of the mothers gave their child an antipyretic and 18% called the physician immediately. In logistic regression analysis, five variables were significantly associated with mothers' concern: the absence of previous information on the management of fever, temperature > 39 degrees C, an only child, mother's low educational level, and mother's residency in the south of Italy. For the request for a physician's visit, of the variables entered, the only explanatory ones were the mother's concern and the absence of previous information on the management of fever., Conclusions: These findings suggest that informing mothers on the definition, consequences, and treatment of fever can significantly improve their confidence in managing fever, as reflected by fewer requests for physicians' visits.