Do trials reduce uncertainty? Assessing impact through cumulative meta-analysis of neonatal RCTs.

OBJECTIVE: To assess the impact of the latest randomized controlled trial (RCT) to each systematic review (SR) in Cochrane Neonatal Reviews. STUDY DESIGN: We selected meta-analyses reporting the typical point estimate of the risk ratio for the primary outcome of the latest study (n=130), mortality (n=128) and the mean difference for the primary outcome (n=44). We employed cumulative meta-analysis to determine the typical estimate after each trial was added, and then performed multivariable logistic regression to determine factors predictive of study impact. RESULTS: For the stated primary outcome, 18% of latest RCTs failed to narrow the confidence interval (CI), and 55% failed to decrease the CI by ⩾20%. Only 8% changed the typical estimate directionality, and 11% caused a change to or from significance. Latest RCTs did not change the typical estimate in 18% of cases, and only 41% changed the typical estimate by at least 10%. The ability to narrow the CI by >20% was negatively associated with the number of previously published RCTs (odds ratio 0.707). Similar results were found in analysis of typical estimates for the outcomes of mortality and mean difference. CONCLUSION: Across a broad range of clinical questions, the latest RCT failed to substantially narrow the CI of the typical estimate, to move the effect estimate or to change its statistical significance in a majority of cases. Investigators and grant peer review committees should consider prioritizing less-studied topics or requiring formal consideration of optimal information size based on extant evidence in power calculations.

Prospective economic evaluation alongside the non-invasive ventilation trial.

OBJECTIVE: To determine the cost-effectiveness of nasal continuous positive pressure (nCPAP) compared with nasal intermittent positive pressure ventilation (NIPPV) in the context of the reported randomized clinical trial. STUDY DESIGN: Using patient-level data from the clinical trial, we undertook a prospectively planned economic evaluation. We measured costs, from a third-party payer perspective in all patients, and from a societal perspective in a subgroup with a time horizon through the earlier of discharge, death or 44 weeks post-menstrual age. RESULTS: From the third-party payer perspective, the mean cost of hospitalization per infant was statistically similar, $143 745 in the NIPPV group compared to $140 403 in the nCPAP group. Cost-effectiveness evaluation revealed a 61% probability that NIPPV is more expensive and less effective than nCPAP. Similar results were found in subgroup analysis from a societal perspective. CONCLUSION: In addition to being clinically equivalent, economic evaluation confirms that NIPPV, as employed in this trial, is also not economically favorable.

Cost consciousness among physicians in the neonatal intensive care unit.

OBJECTIVE: The objectives of this study were (1) to describe the prevalence and correlates of cost consciousness among physician providers in neonatology and (2) to describe knowledge of cost of common medications, laboratory/imaging evaluations, hospitalization costs and reimbursements. STUDY DESIGN: A 54-item survey was administered to members of the Section on Neonatal-Perinatal Medicine of the American Academy of Pediatrics. RESULTS: Of the 602 participants, 37% reported cost consciousness in decision making. Adjusting for years in practice, gender, training level, type of practice setting and region of practice, formalized education about costs was associated with increased cost consciousness in practice (adjusted odds ratio (AOR): 3.4; 95% confidence interval (CI): 1.2 to 9.8). Working in a private practice setting was also associated with increased cost consciousness when ordering laboratory (AOR: 3.0; (95% CI: 1.2 to 7.6)) or imaging tests (AOR: 2.0; 95% CI: 1.0 to 4.8). CONCLUSIONS: We found variation in knowledge of cost. Formal education about costs and working in a private practice setting were associated with increased cost consciousness.

NPHP3 mutations are associated with neonatal onset multiorgan polycystic disease in two siblings.

Two siblings with a severe multiorgan polycystic disease presenting in the neonatal period were identified. Their genetic testing identified compound heterozygous NPHP3 gene mutations, parents being heterozygous carriers. The mutations included a splice-site (c.958-2A>G) and a missense mutation (c.2342G>A; p.G781D), both being extremely rare. NPHP3 encodes for nephrocystin 3 present on the cilia-centrosome complex. We hypothesize that these mutations lead to defective cilia-based signaling, required for normal development of the renal, pancreatic, biliary and portal system. This report outlines a rare neonatal ciliopathy presentation of NPHP3 mutations leading to severe multiorgan failure in two siblings.

Near-infrared spectroscopy versus magnetic resonance imaging to study brain perfusion in newborns with hypoxic-ischemic encephalopathy treated with hypothermia.

BACKGROUND: The measurement of brain perfusion may provide valuable information for assessment and treatment of newborns with hypoxic-ischemic encephalopathy (HIE). While arterial spin labeled perfusion (ASL) magnetic resonance imaging (MRI) provides noninvasive and direct measurements of regional cerebral blood flow (CBF) values, it is logistically challenging to obtain. Near-infrared spectroscopy (NIRS) might be an alternative, as it permits noninvasive and continuous monitoring of cerebral hemodynamics and oxygenation at the bedside. OBJECTIVE: The purpose of this study is to determine the correlation between measurements of brain perfusion by NIRS and by MRI in term newborns with HIE treated with hypothermia. DESIGN/METHODS: In this prospective cohort study, ASL-MRI and NIRS performed during hypothermia were used to assess brain perfusion in these newborns. Regional cerebral blood flow (CBF) values, measured from 1-2 MRI scans for each patient, were compared to mixed venous saturation values (SctO2) recorded by NIRS just before and after each MRI. Analysis included groupings into moderate versus severe HIE based on their initial background pattern of amplitude-integrated electroencephalogram. RESULTS: Twelve concomitant recordings were obtained of seven neonates. Strong correlation was found between SctO2 and CBF in asphyxiated newborns with severe HIE (r=0.88; p value=0.0085). Moreover, newborns with severe HIE had lower CBF (likely lower oxygen supply) and extracted less oxygen (likely lower oxygen demand or utilization) when comparing SctO2 and CBF to those with moderate HIE. CONCLUSIONS: NIRS is an effective bedside tool to monitor and understand brain perfusion changes in term asphyxiated newborns, which in conjunction with precise measurements of CBF obtained by MRI at particular times, may help tailor neuroprotective strategies in term newborns with HIE.

Cost and resource implications with serum angiogenic factor estimation in the triage of pre-eclampsia.

OBJECTIVES: To analyse the economic and resource implications of using plasma soluble fms-like tyrosine kinase-1 s(Flt1) and placenta growth factor (PlGF) measurements in pre-eclampsia evaluation and management. DESIGN: Retrospective cost analysis of our prospective cohort study. SETTING: Boston, Massachusetts (USA). POPULATION: Women (n = 176) presenting to the hospital at <34 weeks of gestation for evaluation of possible pre-eclampsia during 2009-10. Cases without complete cost or outcome data (n = 9) and re-enrolments (n = 18) were excluded. METHODS: Modelled comparisons between the standard approach (combination of blood pressure, urinary protein excretion, alanine aminotransferase and platelet counts) and a novel approach (ratio of plasma sFlt1 and PlGF) using actual hospital data converted to 2012 US dollars in accordance with the Centers for Medicare and Medicaid Services. MAIN OUTCOME MEASURES: Direct 2-week costs and resource use by groups having true or false positive and negative test results for adverse outcomes according to approach. RESULTS: The improved specificity of the novel approach decreased the proportion of women falsely labelled as test-positive from 42.3% (34.4-50.2%) to 4.0% (0.85-7.15%) and increased the proportion correctly labelled as test-negative from 23.5% (16.7-30.3%) to 61.7% (53.9-69.5%). This could potentially reduce average per-patient costs by $1215. Substantial quantities of resources [47.2% (35.7-58.7%) of antenatal admissions and 72.5% (68.0-77.0%) of tests for fetal wellbeing] were unnecessarily used for women who were truly negative. A proportion of iatrogenic preterm deliveries among women with negative results was potentially avoidable representing further cost and resource savings. CONCLUSIONS: Clinical use of the plasma sFlt1 and PlGF ratio improves risk stratification among women presenting for pre-eclampsia evaluation and has the potential to reduce costs and resource use.

Neonatal intensive care unit discharge preparation, family readiness and infant outcomes: connecting the dots.

Neonatal intensive care unit (NICU) discharge readiness is defined as the masterful attainment of technical skills and knowledge, emotional comfort, and confidence with infant care by the primary caregivers at the time of discharge. NICU discharge preparation is the process of facilitating comfort and confidence as well as the acquisition of knowledge and skills to successfully make the transition from the NICU to home. In this paper, we first review the literature about discharge readiness as it relates to the NICU population. Understanding that discharge readiness is achieved, in part, through successful discharge preparation, we then outline an approach to NICU discharge preparation.

The impact of maternal characteristics on the moderately premature infant: an antenatal maternal transport clinical prediction rule.

OBJECTIVE: Moderately premature infants, defined here as those born between 30°/7 and 346/7 weeks gestation, comprise 3.9% of all births in the United States and 32% of all preterm births. Although long-term outcomes for these infants are better than for less mature infants, morbidity and mortality are still substantially increased in comparison with infants born at term. There is an added survival benefit resulting from birth at a tertiary neonatal care center, and although many of these infants require tertiary level care, delivery at lower level hospitals and subsequent neonatal transfer are still common. Our primary aim was to determine the impact of maternal characteristics and antenatal medical management on the early neonatal course of the moderately premature infant. The secondary aim was to create a clinical prediction rule to determine which infants require intubation and mechanical ventilation in the first 24 h of life. Such a prediction rule could inform the decision to transfer maternal-fetal patients before delivery to a facility with a Level III neonatal intensive care unit (NICU), where optimal care could be provided without the requirement for a neonatal transfer. STUDY DESIGN: Data for this analysis came from the cohort of infants in the Moderately Premature Infant Project (MPIP) database, a multicenter cohort study of 850 infants born at gestational age 30°/7 and 346/7 weeks, with birth weight between 591 to 3540 g. [corrected], who were discharged to home alive. We built a logistic regression model to identify maternal characteristics associated with need for tertiary care, as measured by administration of surfactant. Using statistically significant covariates from this model, we then created a numerical decision rule to predict need for tertiary care. RESULT: In multivariate modeling, four factors were associated with reduction in the need for tertiary care, including non-White race (odds ratio (OR)=0.5, (0.3, 0.7)), older gestational age, female gender (OR=0.6 (0.4, 0.8)) and use of antenatal corticosteroids (OR=0.5, (0.3, 0.8)). The clinical prediction rule to discriminate between infants who received surfactant, versus those who did not, had an area under the curve of 0.77 (0.73, 0.8). CONCLUSION: Four antenatal risk factors are associated with a requirement for Level III NICU care as defined by the need for surfactant administration. Future analyses will examine a broader spectrum of antenatal characteristics and revalidate the prediction rule in an independent cohort.