Matthew A. Rysavy

Between-Hospital Variation in Treatment and Outcomes in Extremely Preterm Infants

BACKGROUND Between-hospital variation in outcomes among extremely preterm infants is largely unexplained and may reflect differences in hospital practices regarding the initiation of active lifesaving treatment as compared with comfort care after birth. METHODS We studied infants born between April 2006 and March 2011 at 24 hospitals included in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Data were collected for 4987 infants born before 27 weeks of gestation without congenital anomalies. Active treatment was defined as any potentially lifesaving intervention administered after birth. Survival and neurodevelopmental impairment at 18 to 22 months of corrected age were assessed in 4704 children (94.3%). RESULTS Overall rates of active treatment ranged from 22.1% (interquartile range [IQR], 7.7 to 100) among infants born at 22 weeks of gestation to 99.8% (IQR, 100 to 100) among those born at 26 weeks of gestation. Overall rates of survival and survival without severe impairment ranged from 5.1% (IQR, 0 to 10.6) and 3.4% (IQR, 0 to 6.9), respectively, among children born at 22 weeks of gestation to 81.4% (IQR, 78.2 to 84.0) and 75.6% (IQR, 69.5 to 80.0), respectively, among those born at 26 weeks of gestation. Hospital rates of active treatment accounted for 78% and 75% of the between-hospital variation in survival and survival without severe impairment, respectively, among children born at 22 or 23 weeks of gestation, and accounted for 22% and 16%, respectively, among those born at 24 weeks of gestation, but the rates did not account for any of the variation in outcomes among those born at 25 or 26 weeks of gestation. CONCLUSIONS Differences in hospital practices regarding the initiation of active treatment in infants born at 22, 23, or 24 weeks of gestation explain some of the between-hospital variation in survival and survival without impairment among such patients. (Funded by the National Institutes of Health.).

Survival and neurodevelopmental outcomes among periviable infants

BACKGROUND Data reported during the past 5 years indicate that rates of survival have increased among infants born at the borderline of viability, but less is known about how increased rates of survival among these infants relate to early childhood neurodevelopmental outcomes. METHODS We compared survival and neurodevelopmental outcomes among infants born at 22 to 24 weeks of gestation, as assessed at 18 to 22 months of corrected age, across three consecutive birth‐year epochs (2000–2003 [epoch 1], 2004–2007 [epoch 2], and 2008–2011 [epoch 3]). The infants were born at 11 centers that participated in the National Institute of Child Health and Human Development Neonatal Research Network. The primary outcome measure was a three‐level outcome — survival without neurodevelopmental impairment, survival with neurodevelopmental impairment, or death. After accounting for differences in infant characteristics, including birth center, we used multinomial generalized logit models to compare the relative risk of survival without neurodevelopmental impairment, survival with neurodevelopmental impairment, and death. RESULTS Data on the primary outcome were available for 4274 of 4458 infants (96%) born at the 11 centers. The percentage of infants who survived increased from 30% (424 of 1391 infants) in epoch 1 to 36% (487 of 1348 infants) in epoch 3 (P<0.001). The percentage of infants who survived without neurodevelopmental impairment increased from 16% (217 of 1391) in epoch 1 to 20% (276 of 1348) in epoch 3 (P=0.001), whereas the percentage of infants who survived with neurodevelopmental impairment did not change significantly (15% [207 of 1391] in epoch 1 and 16% [211 of 1348] in epoch 3, P=0.29). After adjustment for changes in the baseline characteristics of the infants over time, both the rate of survival with neurodevelopmental impairment (as compared with death) and the rate of survival without neurodevelopmental impairment (as compared with death) increased over time (adjusted relative risks, 1.27 [95% confidence interval {CI}, 1.01 to 1.59] and 1.59 [95% CI, 1.28 to 1.99], respectively). CONCLUSIONS The rate of survival without neurodevelopmental impairment increased between 2000 and 2011 in this large cohort of periviable infants. (Funded by the National Institutes of Health and others; ClinicalTrials.gov numbers, NCT00063063 and NCT00009633.)

Reporting outcomes of extremely preterm births

Published reports of extremely preterm birth outcomes provide important information to families, clinicians, and others and are widely used to make clinical and policy decisions. Misreporting or misunderstanding of outcome reports may have significant consequences. This article presents 7 recommendations to improve reporting of extremely preterm birth outcomes in both the primary and secondary literature. The recommendations should facilitate clarity in communication about extremely preterm birth outcomes and increase the value of existing and future work in this area.

Mortality among Patients with Methicillin-Resistant Staphylococcus aureus USA300 versus Non-USA300 Invasive Infections: A Meta-Analysis

BACKGROUND Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) has been found to be epidemiologically and microbiologically distinct from healthcare-associated MRSA. Most CA-MRSA infections are not invasive; however, fatal outcomes have been reported among healthy people with CA-MRSA invasive infections. Epidemiological studies have attributed a major burden of CA-MRSA infections in the United States to the predominant clone USA300. We investigated the association between USA300 invasive infections and mortality by conducting a systematic review and meta-analysis of studies that reported mortality rates associated with USA300 strains. METHODS We searched PubMed, bibliographies of other publications, and gray literature between January 2001 and December 2013. Observational studies of patients with an invasive MRSA infection were included. The exposure of interest was presence of USA300 invasive infection. Studies were included only if they provided MRSA PFGE types and if corresponding mortality data were the measured outcome. We pooled crude odds ratios (cORs) using a random-effects model. Woolf test of homogeneity and Q and I(2) statistics were assessed. RESULTS Of 574 articles identified by the search strategy, 8 met the inclusion criteria. Risk of mortality was significantly lower among patients with USA300 MRSA infections (pooled cOR, 0.63 [95% confidence interval (CI)], 0.49-0.81). There was a moderate degree of heterogeneity among study results (P = .29; I(2) = 18%). Results were observed to be heterogeneous due to study design, quality of studies, and definition of mortality. CONCLUSIONS MRSA invasive infection with USA300 does not appear to be associated with higher mortality compared with infections due to non-USA300 strains. Nevertheless, larger well-designed studies are warranted to further evaluate this association.

The Problem and Promise of Prognosis Research

A recent article referred to diagnosis as “the other half of medicine.”1 But there is more than therapy and diagnosis to medicine. Patients and their families want to know answers to questions like “Will she live?” “Will this happen again?” and “How long until we can return home?” Prognosis—the act of foretelling the course of health or illness—has historically played a major role in medicine2 and remains relevant today. Consider, for example, the current statin guidelines, which no longer recommend therapy on the sole diagnosis of hypercholesterolemia but on a patient’s risk for future disease.3 In broad terms, the importance of prognosis in medical decision making informs recent debates about the appropriateness of interventions for precancerous breast tissues, prostatespecific antigen screening for prostate cancer, and, in our area of research, counseling and intervention surrounding extremely preterm birth.4 In this Viewpoint, we explore difficulties in conducting and interpreting prognosis research to guide clinical practice and offer suggestions to improve the approach to this important aspect of medicine.

Prognosis as an Intervention

This article elaborates on how neonatologists and perinatologists might conceive of prognosis as an intervention with outcomes relevant to patients, families, and society at large and highlights aspects of this important area of practice requiring further study.

Global Variation in Neonatal Intensive Care: Does It Matter?

More than 60 years later, studies continue to report marked variation in perinatal and neonatal care among centers, regions, and countries. Consider, for example, the variation in using vitamin A to prevent bronchopulmonary dysplasia, antenatal corticosteroids to promote fetal maturation, and indomethacin to treat patent ductus arteriosus. In this volume of The Journal, Shah et al report results from the International Network for Evaluating Outcomes for Neonates, a collaboration of national neonatal networks in 9 high-income countries: Australia, New Zealand, Canada, Israel, Japan, Spain, Sweden, Switzerland, and the United Kingdom. The investigators examined between-country differences in demographic characteristics, perinatal care, mortality, and serious neonatal morbidities among infants born at 24 0/7 to 31 6/7 weeks of gestation with a birth weight less than 1500 g from 2007 to 2010. The primary outcome was a composite of mortality before discharge, severe intraventricular hemorrhage or periventricular echodensity or echolucency, bronchopulmonary dysplasia, or retinopathy of prematurity that was treated. Comparisons of the primary composite outcome among countries were adjusted for several factors including gestational age and birth weight, as well as clinical care exposures including antenatal steroids and cesarean delivery. The study population of 58 004 infants comprised a large, but incomplete, proportion of births within each country; population coverage of participating networks varied from 53% to 97% for infants weighing less than 1500 g at birth. There was substantial variation in the several aspects of perinatal care evaluated. Antenatal steroid exposure ranged from 49% in Japan to 90% in Australia and New Zealand. Cesarean delivery ranged from 47% in the United Kingdom to 84% in Switzerland. The frequency of the composite primary outcome ranged from 26% in Switzerland to 42% in the United Kingdom. Two-fold or greater differences in the rates of outcomes, including death, bronchopulmonary dysplasia, and severe intraventricular hemorrhage, were observed among countries. After controlling for baseline characteristics of infants, there remained significant differences in the risk of mortality or morbidity for infants among specific network countries. What does this variation mean? Does it matter? The betweencountry comparisons in this study should be viewed with caution. Population coverage, transfer policies, delivery room deaths, outcome definitions, and the amount of missing data varied among countries. As the authors note, the standardized ratios are not directly comparable with one another and must be interpreted in light of these factors. However, the results of this study raise several questions. It would be interesting to understand, for example, why networks in Japan and Spain had similar frequencies of the primary outcome (37% and 38%, respectively) yet, corresponding inhospital mortality was 5% in Japan and 17% in Spain. Are these differences spurious, caused by differences in data collection or referral systems? Or do they reflect differences in processes of care? It is not possible to answer these questions from the available data. Further work by the collaborative might look at other important neonatal morbidities such as necrotizing enterocolitis and late-onset sepsis, which were excluded from this analysis, as well as between-country differences in the care and outcomes of infants born before 24 weeks’ gestation, which, as the authors note, are substantial. Additional studies evaluating trends over time could provide the neonatal community with a global overview of changes in outcomes and intervention in neonatal intensive care. Many efforts to improve the quality of neonatal care focus on identifying undesired variations in outcomes and reducing them. Several large networks, beyond those included in this study, have demonstrated the importance of standardized data collection methods to permit detailed comparisons of neonatal practices and outcomes among member sites. Beyond generating important hypotheses, as in Silverman’s example, findings of variation have spurred quality improvement initiatives and implementation science studies to improve adherence to evidence-based management. The International Network for Evaluating Outcomes for Neonates investigators have taken important steps to organize this large collaborative to use individual patient data for global comparisons of neonatal intensive care processes and outcomes. Although the results of this study do not, by themselves, have direct implications for clinical practice, they point to possibilities for future efforts to improve neonatal intensive care. ■

Lectures and the hidden curriculum.

Editor – We read with interest Dr Smith’s recent commentary regarding lecture attendance in the pre-clinical curriculum. We agree that the first 2 years of medical school are formative and influence students’ future professional behaviours. However, we submit that the issue of lecture attendance is attributable to far more than students’ lifestyle preferences and involves the medium of lecture itself.

Changing outcomes, changing policies for periviable births

MA Rysavy, JE Tyson, BJ Stoll a Department of Pediatrics, University of Wisconsin Hospital and Clinics, Madison, WI, USA b Center for Clinical Research and Evidence-Base Medicine, Department of Pediatrics, University of Texas Health Science Center – Medical School, Houston, TX, USA c John P. and Katherine G. McGovern Medical School, University of Texas Health Science Center at Houston – Medical School, Houston, TX, USA

Community-Acquired Pneumonia and Proton Pump Inhibitors

To the Editors:—We read with interest the article by Jena and colleagues regarding the possibility of residual confounding in the association of proton pump inhibitors (PPIs) and community-acquired pneumonia (CAP). Specifically, we appreciated the argument for “falsification analysis,” which Jena has discussed elsewhere. The notion that a hypothesized causal relationship between an exposure and one outcome can be weakened or strengthened by observing whether the exposure is associated with various other “implausible” outcomes has previously been described as the “specificity” criterion for causality. Notably, this criterion has a long and debated history of use in epidemiological research. We agree with the authors that it deserves further attention in causal interpretations of observational data. However, this method cannot replace other standard considerations in observational data analysis. For example, in this study, the authors base their conclusions about confounding on an association between quarterly claims for PPIs and disease diagnoses without determining when the events occurred in relationship to each other. They do not address the most fundamental feature of any causal relationship—that exposure precedes disease. This leaves numerous possible explanations for why PPI claims may be associated with the “implausible” outcomes under consideration. The analysis here may merely show that prescriptions for PPIs are more likely to appear after a healthcare encounter. Other observational studies evaluating the relationship between PPIs and CAP accounted for temporality and drug dose and differentiated incident from prevalent PPI use, finding important differences related to these factors. Accounting for these factors in the current study would allow a more valid comparison with existing evidence. We agree with the authors that the criterion of specificity may be a useful tool to evaluate causal relationships in observational studies. However, we submit that it should not distract from other important considerations in determining causality.To the Editors:—We read with interest the article by Jena and colleagues regarding the possibility of residual confounding in the association of proton pump inhibitors (PPIs) and community-acquired pneumonia (CAP).1 Specifically, we appreciated the argument for “falsification analysis,” which Jena has discussed elsewhere.2