BackgroundVasopressin (AVP) and terlipressin (TP) have been used as last-line therapy in refractory shock in children. However, the efficacy and safety profiles of AVP and TP have not been determined in pediatric refractory shock of different origins. We aimed to assess the efficacy and safety of the addition of AVP/TP therapy in pediatric refractory shock of all causes compared to conventional therapy with fluid resuscitation and vasopressor and inotropic therapy.MethodsWe conducted a systematic review, meta-analysis, and trial sequential analysis (TSA) comparing AVP and TP to conventional therapy. MEDLINE, EMBASE, Cochrane Library, and ClinicalTrials.gov were searched up to February 2016. The systematic review included all reports of AVP/TP use in the pediatric population. Reports of clinical trials were pooled using random-effects models and TSA. Main outcomes were mortality and tissue ischemia.ResultsThree randomized controlled trials and five “before-and-after clinical” trials (without comparator) met the inclusion criteria. Among 224 neonates and children (aged 0 to 18 years) with refractory shock, 152 received therapy with AVP or TP. Pooled analyses showed no association between AVP/TP treatment and mortality (relative risk (RR),1.19; 95% confidence interval (CI), 0.71–2.00), length of stay in the pediatric intensive care unit (PICU) (mean difference (MD), –3.58 days; 95% CI, –9.05 to 1.83), and tissue ischemia (RR, 1.48; 95% CI, 0.47–4.62). In TSA, no significant effect on mortality and risk for developing tissue ischemia was observed with AVP/TP therapy.ConclusionOur results emphasize the lack of observed benefit for AVP/TP in terms of mortality and length of stay in the PICU, and suggest an increased risk for ischemic events. Our TSA suggests that further large studies are necessary to demonstrate and establish benefits of AVP/TP in children.PROSPERO registry: CRD42016035872Electronic supplementary materialThe online version of this article (doi:10.1186/s13054-016-1589-6) contains supplementary material, which is available to authorized users.

Acetaminophen is the most commonly used analgesic and antipyretic during pregnancy. Evidence of neuro-disruptive properties is accumulating. Therefore, we sought to evaluate the risk for attention deficit hyperactivity disorder (ADHD) and autistic spectrum disorder (ASD) in the offspring of women exposed to acetaminophen during pregnancy. We searched MEDLINE, EMBASE, and Cochrane up to January 2017. Data were independently extracted and assessed by two researchers. Seven eligible retrospective cohorts included 132,738 mother and child pairs and with a follow-up period of 3-11 years. Pooled risk ratio (RR) for ADHD was (RR=1.32, 95% CI 1.18,1.45, I2=61%), for ASD (RR=1.23, 95% CI1.13,1.32, I2=17%), and for hyperactivity symptoms (RR=1.23, 95% CI 1.01,1.49, I2=94%). In meta-regression analysis, the association between exposure and ADHD increased with childs' age upon follow-up and with the mean duration of exposure (β=0.0354, 95% CI 0.001,0.07), (β=0.006, 95% CI 0.009,0.01). The available data is of observational nature only. Studies differed gravely in exposure and outcome assessment. Acetaminophen use during pregnancy is associated with an increased risk for ADHD, ASD and hyperactivity symptoms. These findings are concerning, however, results should be interpreted with caution as the available evidence consists of observational studies and susceptible to several potential sources of bias.

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Exposure to SSRIs or SNRIs during pregnancy is associated with an increased risk for PPHN. According to our findings, sertraline ranked as most likely to have the lowest risk for PPHN compared to other SSRIs, suggesting it may have the best safety profile for use in pregnancy in this regard. Further studies are needed to fully establish these results.

Studies reporting an increased risk for cardiac toxicities with macrolide antibiotics have raised concern regarding their cardiovascular safety. We sought to assess the cardiac safety of macrolide antibiotics as a class and of the individual agents by conducting a systematic review and network meta-analysis. Medline, Embase, and the Cochrane Library were searched up to February 2018 for studies reporting on cardiovascular outcomes with macrolides. We followed the PRISMA 2009 guidelines for data selection and extraction. Outcomes were pooled using random-effects models and odds ratios (OR), and 95% confidence intervals (CI) were calculated for arrhythmia, cardiovascular death, and myocardial infarction (MI). A total of 33 studies and data on 22,601,032 subjects were retrieved and included in the current meta-analyses. Macrolide use was not associated with the risk of arrhythmia or cardiovascular mortality. In the primary analysis, macrolide use was associated with a small but statistically significant 15% increase in risk for MI (OR = 1.15 [95% CI, 1.01 to 1.30]). In indirect network meta-analysis, erythromycin and clarithromycin were ranked considerably more likely to be associated with a higher risk for MI and significantly associated with increased risk of MI compared to azithromycin (OR = 1.58 [95% CI, 1.18 to 2.11] and OR = 1.41 [95% CI, 1.11 to 1.81], respectively). Our findings indicate that macrolide antibiotics as a group are associated with a significant risk for MI but not for arrhythmia and cardiovascular mortality. Among the macrolides, erythromycin and clarithromycin were associated with a greater risk of MI. However, it is possible that the association between macrolide use and risk of MI is the result of residual confounding.

CONTEXT: The efficacy and safety of metformin for obesity in children and adolescents remains unclear. OBJECTIVE: To assess the efficacy and safety of metformin via systematic review. DATA SOURCES: Data sources included PubMed, Embase, the Cochrane Library, Scopus, and ClincalTrials.gov (inception to November 2019). STUDY SELECTION: We selected randomized controlled trials (RCTs) in which researchers assessed the efficacy and safety of metformin with lifestyle interventions, compared with a placebo with lifestyle interventions, in children and adolescents with obesity. DATA EXTRACTION: Two researchers independently extracted data and assessed quality. The primary outcomes were mean changes from baseline in BMI, BMI z score, homeostatic model assessment of insulin resistance, and gastrointestinal adverse effects. RESULTS: Twenty-four RCTs (1623 patients; range: 16 to 151) were included. Ages ranged from 4 to 19 years, and follow-up ranged from 2 months to 2 years. Metformin resulted in a modest decrease in BMI (range of mean values: −2.70 to 1.30 vs −1.12 to 1.90), BMI z score (range of mean values: −0.37 to −0.03 vs −0.22 to 0.15), and homeostatic model assessment of insulin resistance (range of mean values: −3.74 to 1.00 vs −1.40 to 2.66). Metformin resulted in a higher frequency of gastrointestinal adverse effects (range: 2% to 74% vs 0% to 42%). LIMITATIONS: The available evidence is of varying quality, with high heterogeneity between trials, suggesting some uncertainty in the benefits of metformin in this population. CONCLUSIONS: With this systematic review of RCTs, we suggest that metformin has modest but favorable effects on weight and insulin resistance and a tolerable safety profile among children and adolescents with obesity.

Background:The association between acetaminophen use during pregnancy and the development of attention deficit hyperactivity disorder (ADHD) in the offspring may be due to bias. Objectives:The primary objective was to assess the role of potential unmeasured confounding in the estimation of the association between acetaminophen use during pregnancy and the risk of ADHD, through bias analysis. The secondary objective was to assess the roles of selection bias and exposure misclassification. Data sources:We searched MEDLINE, Embase, Scopus, and the Cochrane Library up to December 2018. Study selection and data extraction:We included observational studies examining the association between acetaminophen use during pregnancy and the risk of ADHD. Synthesis:We meta-analysed data across studies, using random-effects model. We conducted a bias analysis to studies that did not adjust for important confounders, to explore systematic errors related to unmeasured confounding, selection bias, and exposure misclassification. Results:The search resulted in seven studies included in our meta-analysis. When adjusted estimates were pooled across all studies, the risk ratio (RR) for ADHD was 1.35 (95% confidence interval [CI] 1.25, 1.46; I 2 = 48%). Sensitivity analysis for unmeasured confounding in this meta-analysis showed that a confounder of 1.69 on the RR scale would reduce to 10% the proportion of studies with a true effect size of RR >1.10. Unmeasured confounding bias analysis decreased the point estimate in five of the seven studies and increased in two studies, suggesting that the observed association could be confounded by parental ADHD. Unadjusted and bias-corrected risk ratios (bcRRs) were: RR = 1.34, bcRR = 1.13; RR = 1.51, bcRR = 1.17; RR = 1.63, bcRR = 1.38; RR = 1.44, bcRR = 1.17; RR = 1.16, bcRR = 1.18; RR = 1.25, bcRR = 1.05;and RR = 0.99, bcRR = 1.18. Conclusions:Bias analysis suggests that the previously reported association between acetaminophen use during pregnancy and an increased risk of ADHD in the offspring may be due to unmeasured confounding. Our ability to conclude a causal association is limited. K E Y W O R D Sacetaminophen, ADHD, bias, confounding, pregnancy

PROSPERO CRD42017060573.