A failed attempt to conduct an individual patient data meta-analysis

A study-level meta-analysis has shown that proton magnetic resonance spectroscopy is a promising prognostic marker in neonatal hypoxic-ischemic encephalopathy. An individual patient data meta-analysis could yield a prognostic tool with improved accuracy enabling well-founded clinical decisions. Our request to share patient data remained unanswered by five out of 18 research groups. Another four declined collaboration for various reasons, including own reanalysis of the data, and lack of parental consent. With less than 40% of the individual patient data available, we refrained from pursuing the proposed study. As future patients may benefit from it, policies mandating data sharing should be introduced

Chorioamnionitis appears not to be a Risk Factor for Patent Ductus Arteriosus in Preterm Infants: A Systematic Review and Meta-Analysis

The contribution of chorioamnionitis (CA) to mortality and morbidity in preterm infants is difficult to assess because observational studies frequently present significant differences in baseline characteristics of the infants exposed or non-exposed to CA. In an attempt to perform a thorough assessment of the possible association between CA and patent ductus arteriosus (PDA) in preterm infants, we conducted a meta-analysis in which adjusted odds ratios (ORs) were pooled and we analyzed the effects of potential confounders, such as gestational age (GA) or birth weight (BW). We identified 45 relevant studies (27186 patients, 7742 CA cases). Random effects meta-analysis of crude ORs showed a significant positive association between CA and PDA (OR 1.352, 95% CI 1.172 to 1.560). Adjusted ORs were reported in 11 studies (19577 infants). Meta-analysis of these studies showed a significant negative association between CA and PDA (OR 0.802, 95% CI 0.751 to 0.959). Meta-regression showed that the differences in GA or BW between the CA-exposed and non-exposed groups were significantly correlated with the effect size of the association between PDA and CA. In conclusion, our study confirms that confounders need to be taken into account when assessing the association between CA and clinical outcomes in preterm infants

The bioavailability and maturing clearance of doxapram in preterm infants

Background: Doxapram is used for the treatment of apnea of prematurity in dosing regimens only based on bodyweight, as pharmacokinetic data are limited. This study describes the pharmacokinetics of doxapram and keto-doxapram in preterm infants. Methods: Data (302 samples) from 75 neonates were included with a median (range) gestational age (GA) 25.9 (23.9–29.4) weeks, bodyweight 0.95 (0.48–1.61) kg, and postnatal age (PNA) 17 (1–52) days at the start of continuous treatment. A population pharmacokinetic model was developed using non-linear mixed-effects modelling (NONMEM®). Results: A two-compartment model best described the pharmacokinetics of doxapram and keto-doxapram. PNA and GA affected the formation clearance of keto-doxapram (CL FORMATION KETO-DOXAPRAM) and clearance of doxapram via other routes (CL DOXAPRAM OTHER ROUTES). For a median individual of 0.95 kg, GA 25.6 weeks, and PNA 29 days, CL FORMATION KETO-DOXAPRAM was 0.115 L/h (relative standard error (RSE) 12%) and CL DOXAPRAM OTHER ROUTES was 0.645 L/h (RSE 9%). Oral bioavailability was estimated at 74% (RSE 10%). Conclusions: Dosing of doxapram only based on bodyweight results in the highest exposure in preterm infants with the lowest PNA and GA. Therefore, dosing may need to be adjusted for GA and PNA to minimize the risk of accumulation and adverse events. For switching to oral therapy, a 33% dose increase is required to maintain exposure. Impact: Current dosing regimens of doxapram in preterm infants only based on bodyweight result in the highest exposure in infants with the lowest PNA and GA.Dosing of doxapram may need to be adjusted for GA and PNA to minimize the risk of accumulation and adverse events.Describing the pharmacokinetics of doxapram and its active metabolite keto-doxapram following intravenous and gastroenteral administration enables to include drug exposure to the evaluation of treatment of AOP.The oral bioavailability of doxapram in preterm neonates is 74%, requiring a 33% higher dose via oral than intravenous administration to maintain exposure