A population pharmacokinetic model for escitalopram and its major metabolite in depressive patients during the perinatal period: Prediction of infant drug exposure through breast milk.

BACKGROUND AND OBJECTIVES: Escitalopram (SCIT) is frequently prescribed to breastfeeding women. Available information on SCIT excretion into breast milk is based on heterogeneous and incomplete data. A population pharmacokinetic model that aimed to better characterize maternal and infant exposure to SCIT and its metabolite was developed. METHODS: The study population was composed of women treated by SCIT or racemic citalopram and enrolled in the multicenter prospective cohort study SSRI-Breast Milk study (ClinicalTrial.gov NCT01796132). A joint structural model was first built for SCIT and S-desmethylcitalopram (SDCIT) in plasma using NONMEM and the milk-to-plasma ratio (MPR) was estimated by adding the drug breast milk concentrations. The effect of different influential covariates was tested and the average drug exposure with variability through breastfeeding was predicted under various conditions by simulation. RESULTS: The study enrolled 33 patients treated with SCIT or racemic citalopram who provided 80 blood and 104 milk samples. Mean MPR for both parent drug and metabolite was 1.9. Increased milk fat content was significantly associated with an increased drug transfer into breast milk (+28% for SCIT and +18% for SDCIT when fat amount doubles from 3.1 to 6.2 g/100 mL). Simulations suggested that an exclusively breastfed infant would ingest daily through breast milk 3.3% of the weight-adjusted maternal SCIT dose on average. CONCLUSION: The moderate between-subject variability in milk concentration of SCIT and the limited exposure to escitalopram through breast milk observed provide reassurance for treated mothers of breastfed healthy infants.

Reducing waste in pediatric clinical research.

The importance of reducing waste and increasing value when conducting research has been emphasized by a series of articles published in the Lancet in 2014. A survey indicates that, one year later, these articles have not influenced how research is conducted. In this review, we explore four stages described by Moher et al. in research production that lead to waste. We show that all four stages including, questions relevant to users, appropriate design conduct and analysis, accessible full research, unbiased and usable reports, efficient research regulation and management of biomedical research are also producing an important waste in pediatric research. We conclude that methods to improve research quality and limit waste need to be implemented in pediatric research and recognized by authorities as a priority.

Unlicensed/Off-Label Drug Prescriptions at Hospital Discharge in Children: An Observational Study Using Routinely Collected Health Data.

BACKGROUND: Unlicensed and off-label (UL/OL) prescriptions have been associated with an increased risk of drug-related problems. Data of their prevalence at hospital discharge remain insufficient. We aimed to describe the prevalence of UL/OL drugs in outpatient prescriptions at discharge in children. METHODS: We conducted a retrospective study using the routinely collected health data of children at discharge from 2014 to 2016. The primary reference source for determining licensed labelling was the summaries of product characteristics (SPCs) in a French industry-independent formulary named Thériaque. We described the characteristics of UL/OL prescriptions at discharge and looked for predictors of UL/OL prescriptions. RESULTS: We included 2536 prescriptions of 479 children. Licensed, OL, and UL prescriptions accounted for 58.6% (95% CI: 56.7-60.5), 39.2% (95% CI: 37.3-41.1), and 2.3% (95% CI: 1.7-2.9), respectively. A total of 323 (74%) children received at least one UL/OL drug. Among the licensed drugs, bronchodilators (8.8%) and analgesics (8.6%), and among the OL drugs, antibiotics (2.8%), were the most prescribed. The younger age of the children and higher number of drugs they received increased the probability of UL/OL prescriptions (unadjusted p-value of ≤0.05). CONCLUSION: The prevalence of UL/OL prescriptions is about 40% at discharge from a pediatric university hospital in France.

Drug-related risk of hospital readmission in children with chronic diseases, a systematic review.

BACKGROUND: Drug-related problems (DRPs) are one of the leading causes of hospital readmissions. Children with chronic diseases are more likely to experience DRPs than adults. The burden and characteristics of drug-related readmissions at and after hospital discharge in children remain unclear. OBJECTIVE: We aimed to summarize the impact of DRPs at and after hospital discharge on the risk of readmissions in children with chronic diseases. METHODS: We conducted a systematic review searching PubMed from inception until January 2022. Study selection criteria were studies assessing the impact of different factors at discharge and after discharge on the risk of hospital readmissions in children with chronic diseases, reporting an assessment of DRPs. DRP could be the only risk factor assessed or one among others. Included studies were assessed with the Risk of Bias in Non-Randomized Studies - of Exposure (ROBINS-E) tool. We summarized the qualitative impact of the reported DRPs on hospital readmission as conclusive (significant association) or inconclusive. RESULTS: Of the 4734 studies initially identified, 13 met inclusion criteria. Eleven studies were retrospective, using electronic health records. The studies assessed the impact of DRPs at or after discharge according to the type of medication (in 6 studies), number of medication (in 5 studies) and medication nonadherence (in 2 studies). From the 44 reported associations between DRPs and the risk of readmission 26 (59% [95% CI, 43%-73%]) were conclusive, of which 81% increased the risk and 19% decreased the risk, and 17 (39% [95% CI, 24%-55%]) were inconclusive. CONCLUSION: The impact of DRPs on hospital readmissions in children with chronic diseases displayed conflicting results, estimated associations having potentially a serious risk of bias. We need more evidence with a lower risk of bias.

Outcomes of pregnancies with preterm premature rupture of membranes occurring before 24 weeks of gestation: An 11-year observational study.

OBJECTIVE: This study describes the fetal and neonatal outcomes and their predictive factors in pregnancies with preterm premature rupture of membranes (PPROM) before 24 weeks of gestation. METHODS: A retrospective study was conducted using the patient database of a tertiary university hospital in Lyon, France. All of the medical data of women diagnosed with PPROM before 24 weeks of gestation from 2008 to 2018 were extracted. R software was used for descriptive and analytical statistics. RESULTS: The study included 78 women. Mean gestational age (GA) at PPROM was 19.6 weeks (13.1 to 23.9 weeks). Fifteen (19.2%) pregnancies were terminated, 37 (47.4%) resulted in intrauterine fetal death (IUFD), and 26 (33.3%) children were born alive at an average of 26.9 weeks of gestation. Fourteen children survived and 12 died after birth; 50% of survivors had pulmonary hypoplasia. Within 7 days after PPROM, 46% of IUFD occurred and 36% of pregnancies ended. PPROM before 20 weeks of gestation and chorioamnionitis are statistically associated with IUFD, whereas a latency period of more than 2 weeks is statistically related to live birth. CONCLUSION: PPROM before 24 weeks of gestation is associated with a high rate of IUFD, preterm birth, and postpartum mortality.

Heterogeneity and Gaps in Reporting Primary Outcomes From Neonatal Trials.

OBJECTIVES: Clear outcome reporting in clinical trials facilitates accurate interpretation and application of findings and improves evidence-informed decision-making. Standardized core outcomes for reporting neonatal trials have been developed, but little is known about how primary outcomes are reported in neonatal trials. Our aim was to identify strengths and weaknesses of primary outcome reporting in recent neonatal trials. METHODS: Neonatal trials including ≥100 participants/arm published between 2015 and 2020 with at least 1 primary outcome from a neonatal core outcome set were eligible. Raters recruited from Cochrane Neonatal were trained to evaluate the trials' primary outcome reporting completeness using relevant items from Consolidated Standards of Reporting Trials 2010 and Consolidated Standards of Reporting Trials-Outcomes 2022 pertaining to the reporting of the definition, selection, measurement, analysis, and interpretation of primary trial outcomes. All trial reports were assessed by 3 raters. Assessments and discrepancies between raters were analyzed. RESULTS: Outcome-reporting evaluations were completed for 36 included neonatal trials by 39 raters. Levels of outcome reporting completeness were highly variable. All trials fully reported the primary outcome measurement domain, statistical methods used to compare treatment groups, and participant flow. Yet, only 28% of trials fully reported on minimal important difference, 24% on outcome data missingness, 66% on blinding of the outcome assessor, and 42% on handling of outcome multiplicity. CONCLUSIONS: Primary outcome reporting in neonatal trials often lacks key information needed for interpretability of results, knowledge synthesis, and evidence-informed decision-making in neonatology. Use of existing outcome-reporting guidelines by trialists, journals, and peer reviewers will enhance transparent reporting of neonatal trials.

Strengthening Reporting of Neonatal Trials.

BACKGROUND AND OBJECTIVES: There is variability in the selection and reporting of outcomes in neonatal trials with key information frequently omitted. This can impact applicability of trial findings to clinicians, families, and caregivers, and impair evidence synthesis. The Neonatal Core Outcomes Set describes outcomes agreed as clinically important that should be assessed in all neonatal trials, and Consolidated Standards of Reporting Trials (CONSORT)-Outcomes 2022 is a new, harmonized, evidence-based reporting guideline for trial outcomes. We reviewed published trials using CONSORT-Outcomes 2022 guidance to identify exemplars of neonatal core outcome reporting to strengthen description of outcomes in future trial publications. METHODS: Neonatal trials including >100 participants per arm published between 2015 to 2020 with a primary outcome included in the Neonatal Core Outcome Set were identified. Primary outcome reporting was reviewed using CONSORT 2010 and CONSORT-Outcomes 2022 guidelines by assessors recruited from Cochrane Neonatal. Examples of clear and complete outcome reporting were identified with verbatim text extracted from trial reports. RESULTS: Thirty-six trials were reviewed by 39 assessors. Examples of good reporting for CONSORT 2010 and CONSORT-Outcomes 2022 criteria were identified and subdivided into 3 outcome categories: "survival," "short-term neonatal complications," and "long-term developmental outcomes" depending on the core outcomes to which they relate. These examples are presented to strengthen future research reporting. CONCLUSIONS: We have identified examples of good trial outcome reporting. These illustrate how important neonatal outcomes should be reported to meet the CONSORT 2010 and CONSORT-Outcomes 2022 guidelines. Emulating these examples will improve the transmission of information relating to outcomes and reduce associated research waste.

Trigger tools to identify adverse drug events in hospitalised children: A systematic review.

AIMS: To identify all available trigger tools applicable to the pediatric population in hospital settings to detect adverse drug events (ADEs) and to describe their performances by positive predictive value (PPV). METHODS: PubMed® was searched until December 2021. The reference sections were also consulted for new articles. Studies were selected when they used one or more triggers to identify AEs and used data on pediatric inpatient settings. Studies mentioning triggers related to AEs that were only caused by care procedures were excluded. Only triggers related to ADEs were included. PPVs of triggers were reported. Mean PPVs were calculated for multi-study triggers. The interest of each trigger in a real-time detection system was assessed. RESULTS: Thirty studies were included. A total of 271 unique triggers were identified, 179 of which were related to drug-induced harms. Among them, 68 could be used for prevention of ADEs, 80 for verification and 31 for reporting. Nineteen triggers (11%) had a mean PPV between 50% and 100%, including 5 that had a 100% PPV. CONCLUSION: The performances of individual triggers need to be more adequately studied. The detection of ADEs through computerized triggers and/or real-time detection systems remains an emerging field, very much needed in children especially, due to frequent off-label use.

Agreement between a regional pharmacovigilance centre and an adjudication committee regarding adverse drug reactions on a cohort of hospitalised children.

BACKGROUND AND PURPOSE: The EREMI project was set up to collect data on adverse drug reactions (ADRs) occurring due to off-label and/or unlicensed drugs prescribed to hospitalised children in France. These events were evaluated by a regional pharmacovigilance centre (RPC) and an adjudication committee (AC). The aim of this study was to assess the agreement between these two different entities on their evaluation of ADRs. EXPERIMENTAL APPROACH: The RPC first validated the ADRs and assessed their causality using the Naranjo scale. The AC assessed then ADRs using all available information, including the RPC evaluation. The agreement on severity and nature of ADRs, role of treatment (suspect or concomitant) and drug causality was calculated using Cohen's nonparametric kappa coefficient (k). KEY RESULTS: Three hundred and eighty-six events were reported in 219 children. The RPC excluded 65 events and validated 321 ADRs. Agreement was very good on nature of ADRs (k=0.85) and role of treatment (k=0.81), moderate on severity of ADRs (k=0.60) and very poor on drug causality (k=0.05). CONCLUSION AND IMPLICATIONS: Agreement between the RPC and the AC was not constant throughout this evaluation. They troubled to agree on severe ADRs and on drug causality.

Reference values for the external genitalia of full-term and pre-term female neonates.

BACKGROUND AND OBJECTIVES: Identifying virilisation of the genitalia in female newborns early during the neonatal period is important to diagnose pathologies. However, there is no clear threshold for clitoromegaly or for the anogenital ratio. The objective of this study was to define reference values for the external genitalia of full-term and pre-term female neonates. DESIGN: This was a prospective study of all females born in the study centre between May 2014 and July 2016. Clitoral length and anogenital ratio were measured in 619 newborns with a gestational age of 24+2 to 41+3 weeks during their first 3 days of life. Associations between the values at day 3 and gestational age, birth weight and other newborn characteristics were examined by linear regression. RESULTS: The mean clitoral length at day 3 of life was 3.69±1.53 mm (n=551; 95th percentile, 6.5 mm; maximum, 8 mm), and the mean anogenital ratio was 0.42±0.09 (95th percentile, 0.58). There was no significant variation with gestational age or birth weight, and no significant difference between the results at day 0 and day 3. CONCLUSION: These results suggest that clitoromegaly can be defined as a clitoral length >6.5 mm. Values ≥8 mm should prompt further investigations. An anogenital ratio >0.6 should be considered a sign of virilisation. Since clitoral size does not vary with gestational age or birth weight, clitoromegaly should not be attributed to prematurity.

Relationship between adverse drug reactions and unlicensed/off-label drug use in hospitalized children (EREMI): A study protocol.

INTRODUCTION: To date, few studies have shown a significant association between off-label drug use and adverse drug reactions (ADRs). The main aims of this study is to evaluate the relationship between adverse drug reactions and unlicensed or off-label drugs in hospitalized children and to provide more information on prescribing practice, the amplitude, consequences of unlicensed or off-label drug use in pediatric inpatients. METHODS: In this multicenter prospective study started from 2013, we use the French summaries of product characteristics in Theriaque (a prescription products guide) as a primary reference source for determining pediatric drug labeling. The detection of ADRs is carried out spontaneously by health professionals and actively by research groups using a trigger tool and patients' electronic health records. The causality between suspected ADRs and medication is evaluated using the Naranjo and the French methods of imputability independently by pharmacovigilance center. All suspected ADRs are submitted for a second evaluation by an independent pharmacovigilance experts. STRENGTH AND LIMITATIONS OF THIS STUDY: For our best knowledge, EREMI is the first large multicenter prospective and objective study in France with an active ADRs monitoring and independent ADRs validation. This study identifies the risk factors that could be used to adjust preventive actions in children's care, guides future research in the field and increases the awareness of physicians in off-label drug use and in detecting and declaring ADRs. As data are obtained through extraction of information from hospital database and medical records, there is likely to be some under-reporting of items or missing data. In this study the field specialists detect all adverse events, experts in pharmacovigilance centers assess them and finally only the ADRs assessed by the independent committee are confirmed. Although we recruit a high number of patients, this observational study is subject to different confounders.

The French Pregnancy Cohort: Medication use during pregnancy in the French population.

PURPOSE: We described the medication use during pregnancy in the French population using the French Pregnancy Cohort (FPC). METHODS: The FPC was built with the sampling of all pregnant women included in the French Echantillon généraliste des bénéficiaires (EGB), which is a 1/97th representative sample of the population covered by the French health insurance. The EGB includes anonymized information on the socio-demographic and medical characteristics of beneficiaries, and the health care services they have received such as diagnoses and procedure codes as well as data on filled reimbursed medication; EGB also includes data on hospital stays in all public and private French health facilities. Each filled prescription record contains information on drug brand and generic names, date of prescription and date of dispensing, quantity dispensed, mode of administration, duration of prescription, dosage, and prescribing physician specialty. FPC includes data on all pregnancies of women in the EGB (2010-2013). Date of entry in the FPC is the first day of pregnancy regardless of pregnancy outcome (spontaneous abortions or planned abortions (with or without medical reasons), deliveries), and data on women are collected retrospectively for a period of one year before pregnancy, and prospectively during pregnancy, and up to one year after delivery. The prevalence of prescribed medications before, during and after pregnancy was compared; comparison was also done between trimesters. Pregnancy outcomes are described and include spontaneous and planned abortions, livebirths, and stillbirths. RESULTS: FPC includes data on 36,065 pregnancies. Among them, 27,253 (75.6%) resulted in a delivery including 201 stillbirths (0.7%). The total number of spontaneous abortions was 6,718 (18.6%), and planned abortions 2,094 (5.8%). The prevalence of filled medication use was 91.1%, 89.9%, and 95.6% before, during and after pregnancy, respectively. Although there was a statistically significant decrease in the proportion of use once the pregnancy was diagnosed (first trimester exposure, 76.4% vs. exposure in the year prior to pregnancy, 91.1% (p < .01)), post-pregnancy medication use was above the pre-pregnancy level (95.6%). Maternal depression was the most prevalent comorbidity during pregnancy (20%), and post-partum depression was higher in those who delivered a stillborn infant (38.8%) as well as in those with a spontaneous (19.5%) or planned abortion (22.4%) compared to those with a liveborn (12.0%). CONCLUSION: FPC is an excellent tool for the study of the risk and benefit of drug use during the perinatal period. FPC has the advantage of including a representative sample of French pregnant women, and study medications only available in France in addition to others available worldwide.

Simultaneous determination of selective serotonin reuptake inhibitors and their main metabolites in human breast milk by liquid chromatography-electrospray mass spectrometry.

A bioanalytical method by high performance liquid chromatography coupled to electrospray mass spectrometry (HPLC-ESI-MS), adapted from a previously published method in plasma, was validated in breast milk for the simultaneous quantification of all antidepressants belonging to the class of selective serotonin reuptake inhibitors (citalopram, fluoxetine, fluvoxamine, paroxetine and sertraline) and their major metabolites (desmethylcitalopram and norfluoxetine). Milk samples (250µl) first underwent protein precipitation followed by solid-phase extraction on a reversed phase/cation exchange sorbent. Analytes were thereafter separated on a XBridge C18 column (2.1mm×100mm; 3.5µm) using a mobile phase composed of ammonium acetate buffer (pH 8.1; 50mM) and acetonitrile in gradient mode. Detection was performed by a single quadrupole mass spectrometer running in selected ion monitoring in positive ionization mode. Method validation covered a wide concentration range of 2-500ng/ml for citalopram, desmethylcitalopram and paroxetine, 5-500ng/ml for sertraline, and 2-1000ng/ml for fluoxetine, norfluoxetine and fluvoxamine. Validation performances such as trueness (90.3-111.6%), repeatability (0.8-9.3%) and intermediate precision (0.9-9.5%) were in agreement with criteria from international guidelines and matrix effects for the analyte/internal standard ratios ranged from 92% to 110% (relative standard deviation <15%). Accuracy profiles (total error of trueness and precision) were lying within the limits of ±30% accepted in bioanalysis. Finally, the method was successfully applied to patient samples collected in a clinical pharmacokinetic study of nursing mothers taking an antidepressant treatment.

Stereoselective determination of citalopram and desmethylcitalopram in human plasma and breast milk by liquid chromatography tandem mass spectrometry.

A high performance liquid chromatography (HPLC) tandem mass spectrometry (MS/MS) method was developed for the simultaneous, stereoselective quantification of the antidepressant citalopram and its active metabolite desmethylcitalopram in human plasma and breast milk. Sample preparation was performed by a two-step approach, including generic protein precipitation with acetonitrile followed by solid phase extraction. Enantiospecific separation of analytes was achieved on a Phenomenex® Lux Cellulose-2 column (4.6mm×150mm; 5µm), using reversed phase chromatography conditions characterized by a gradient elution of ammonium acetate buffer (pH 9.0; 20mM) and acetonitrile at a flow rate of 0.6ml/min. The compounds were detected by a tandem quadrupole mass spectrometer equipped with an electrospray ionization source and operating in multiple reaction monitoring mode. The method was fully validated in both biological fluids over a large concentration range of 0.1-100ng/ml for S-(+)- and R-(-)-citalopram, and 0.3-100ng/ml for S-(+)- and R-(-)-desmethylcitalopram. Trueness (90.0-113.3% and 97.1-103.6%), repeatability (0.9-15.9% and 0.9-8.4%) and intermediate precision (1.3-17.8% and 0.9-9.6%) in plasma and breast milk, respectively, meet international guidelines for method validation. Internal standard-normalized matrix effects ranged between 99 and 101% and 98-105%, respectively. The accuracy profiles (total error of trueness and precision) were mostly within the acceptance limits for biological samples defined as ±30%. The method was successfully applied to patient samples in a clinical trial setting.