Tetsuya Isayama

Comparison of Mortality and Morbidity of Very Low Birth Weight Infants Between Canada and Japan

OBJECTIVE: To compare neonatal outcomes of very low birth weight (VLBW) infants admitted to NICUs participating in the Canadian Neonatal Network and the Neonatal Research Network of Japan. METHODS: Secondary analyses of VLBW infants in both national databases between 2006 and 2008 were conducted. The primary outcome was a composite of mortality or any major morbidity defined as severe neurologic injury, bronchopulmonary dysplasia, necrotizing enterocolitis, or severe retinopathy of prematurity at discharge. Secondary outcomes included individual components of primary outcome and late-onset sepsis. Logistic regression adjusting for confounders was performed. RESULTS: A total of 5341 infants from the Canadian Neonatal Network and 9812 infants from the Neonatal Research Network of Japan were compared. There were higher rates of maternal hypertension, diabetes mellitus, outborn, prenatal steroid use, and multiples in Canada, whereas cesarean deliveries were higher in Japan. Composite primary outcome was better in Japan in comparison with Canada (adjusted odds ratio [AOR] 0.87, 95% confidence interval [CI] 0.79–0.96). The odds of mortality (AOR 0.40, 95% CI 0.34–0.47), severe neurologic injury (AOR 0.57, 95% CI 0.49–0.66), necrotizing enterocolitis (AOR 0.23, 95% CI 0.19–0.29), and late-onset sepsis (AOR 0.22, 95% CI 0.19–0.25) were lower in Japan; however, the odds of bronchopulmonary dysplasia (AOR 1.24, 95% CI 1.10–1.42) and severe retinopathy of prematurity (AOR 1.98, 95%CI 1.69–2.33) were higher in Japan. CONCLUSIONS: Composite outcome of mortality or major morbidity was significantly lower in Japan than Canada for VLBW infants. However, there were significant differences in various individual outcomes identifying areas for improvement for both networks.

Revisiting the Definition of Bronchopulmonary Dysplasia: Effect of Changing Panoply of Respiratory Support for Preterm Neonates

Importance Several definitions of bronchopulmonary dysplasia are clinically used; however, their validity remains uncertain considering ongoing changes in the panoply of respiratory support treatment strategies used within neonatal units. Objective To identify the optimal definition of bronchopulmonary dysplasia that best predicts respiratory and neurodevelopmental outcomes in preterm infants. Design, Setting, and Participants Retrospective cohort study at tertiary neonatal intensive care units. Preterm infants born at less than 29 weeks’ gestation between 2010 and 2011 who were admitted to neonatal intensive care units participating in the Canadian Neonatal Network and completed follow-up assessments in a Canadian Neonatal Follow-Up Network clinic at 18 to 21 months. Exposures Various traditional bronchopulmonary dysplasia criteria based on respiratory status at different postmenstrual ages. Main Outcomes and Measures Serious respiratory morbidity, neurosensory impairment at 18 to 21 months of age, and a composite outcome of respiratory or neurosensory morbidity or death after discharge. Adjusted odds ratios (AORs) and 95% CIs were calculated. Results Of 1914 eligible survivors, 1503 were assessed (mean gestational age was 26.3 weeks; 68% were white, 9% were black, and 23% were other race/ethnicity), 88 had serious respiratory morbidity, 257 infants had neurosensory impairment, and 12 infants died after discharge. Definitions using oxygen requirement alone as the criterion at various postmenstrual ages were less predictive compared with those using the criterion of oxygen/respiratory support (RS) (receiving supplemental oxygen and/or positive-pressure RS); among those, oxygen/RS at 36 weeks had the highest AOR and area under the curve (AUC) for all outcomes. Further analyses of oxygen/RS at each week between 34 and 44 weeks’ postmenstrual age indicated that the predictive ability for serious respiratory morbidity increased from 34 weeks (AOR, 1.8; 95% CI, 0.9-3.4, AUC, 0.721) to 40 weeks (AOR, 6.1; 95% CI, 3.4-11.0; AUC, 0.799). For serious neurosensory impairment, the AOR and AUC at 40 weeks’ PMA (AOR, 1.5, 95% CI, 1.0-2.1; AUC, 0.740) were only marginally below their peak values at 37 weeks’ PMA (AOR, 1.8; 95% CI, 1.3-2.6; AUC, 0.743). Conclusions and Relevance Defining bronchopulmonary dysplasia by the use of oxygen alone is inadequate because oxygen/RS is a better indicator of chronic respiratory insufficiency. In particular, oxygen/RS at 40 weeks’ PMA was identified as the best predictor for serious respiratory morbidity, while it also displayed a good ability to predict neurosensory morbidity at 18 to 21 months.

Scoping review shows wide variation in the definitions of bronchopulmonary dysplasia in preterm infants and calls for a consensus

The use of different definitions for bronchopulmonary dysplasia (BPD) has been an ongoing challenge. We searched papers published in English from 2010 and 2015 reporting BPD as an outcome, together with studies that compared BPD definitions between 1978 and 2015. We found that the incidence of BPD ranged from 6% to 57%, depending on the definition chosen, and that studies that investigated correlations with long‐term pulmonary and/or neurosensory outcomes reported moderate‐to‐low predictive values regardless of the BPD criteria.

Adverse Impact of Maternal Cigarette Smoking on Preterm Infants: A Population-Based Cohort Study.

OBJECTIVE The aim of the study is to examine the impact of exposure to maternal cigarette smoking on neonatal outcomes of very preterm infants. STUDY DESIGN A retrospective cohort study examined preterm infants (<33 weeks gestational age) admitted to the Canadian Neonatal Network centers between 2003 and 2011. Mortality and major morbidities (bronchopulmonary dysplasia, severe intraventricular hemorrhage, necrotizing enterocolitis, and retinopathy) were compared between infants exposed and unexposed to maternal smoking during pregnancy after adjusting for confounders. RESULTS Among 29,051 study infants, 4,053 (14%) were exposed to maternal smoking during pregnancy. Multivariable analysis revealed higher odds of grade 3 or 4 intraventricular hemorrhage or periventricular leukomalacia (adjusted odds ratio [OR]: 1.21, 95% confidence interval [CI]: 1.04-1.41) and bronchopulmonary dysplasia (adjusted OR: 1.16, 95% CI: 1.02-1.33) in the smoking group, while mortality, severe retinopathy, and necrotizing enterocolitis were not significantly different. CONCLUSION Maternal smoking during pregnancy is associated with severe neurological injury and bronchopulmonary dysplasia in preterm infants.

Patent ductus arteriosus management and outcomes in Japan and Canada: comparison of proactive and selective approaches.

OBJECTIVE The aim of this study is to compare patent ductus arteriosus (PDA) management strategies and outcomes between the Neonatal Research Network of Japan (NRNJ) with proactive functional echocardiography and the Canadian Neonatal Network (CNN) with selective conventional echocardiography practice. STUDY DESIGN Retrospective analyses examined very low-birth-weight infants admitted to the NRNJ or CNN in 2006 to 2008. Multivariable logistic regression analyses compared a composite outcome indicating a mortality or major morbidity (severe intraventricular hemorrhage, periventricular leukomalacia, severe retinopathy of prematurity, bronchopulmonary dysplasia, or necrotizing enterocolitis) between networks, according to PDA diagnosis and treatment, and tested the association between PDA treatment and the composite outcome within networks. RESULTS PDA treatment (NRNJ:CNN) with conservative management (8%:16%), indomethacin only (77%:59%), ligation only (1%:13%), or indomethacin and ligation (14%:13%) varied significantly between networks. The composite outcome was lower in NRNJ versus CNN only among infants with PDA (odds ratio: 0.70; 95% confidence interval: 0.62-0.80). Surgical ligation was associated with higher composite outcome only in CNN (odds ratio: 1.79; 95% confidence interval: 1.40-2.28). CONCLUSION Lower composite mortality/morbidity outcome in Japan versus Canada only among infants with PDA, and association of surgical ligation with higher mortality/morbidity only in Canada, suggest differential PDA management and ligation processes contribute to outcome variation.

Socioeconomic inequity in survival for deliveries at 22–24 weeks of gestation

Objective Guidelines recommend individual decision making on resuscitating infants of 22–24 weeks’ gestational age (GA) at birth. When the decision not to resuscitate is made, infants would likely die soon after delivery, and under some circumstances such neonatal deaths may be registered as stillbirths occurring during delivery (intrapartum stillbirth). Thus we assessed whether socioeconomic factors are associated with peridelivery deaths (during or within 1 hour of delivery) of infants delivered at 22–24 weeks’ gestation. Methods We analysed 14 726 singletons of 22–24 weeks’ GA using the 2003–2011 Japanese vital statistics, and assessed how maternal characteristics influence risk of peridelivery death as well as intrauterine fetal death (IUFD) and death after 1 hour of age until 40 weeks postmenstrual age. Results Living in a municipality with low-average income (lowest tertile (risk ratio 1.32, 95% CI 1.20 to 1.44), middle tertile (risk ratio 1.08, 95% CI 0.98 to 1.19)), younger maternal age (age <20 (risk ratio 1.43, 95% CI 1.17 to 1.75), age 20–34 (risk ratio 1.14, 95% CI 1.03 to 1.27)) and having previous live births (risk ratio 1.08, 95% CI 1.01 to 1.17) increased risk of peridelivery deaths, but did not increase risk of IUFD or deaths after 1 hour of age. Peridelivery death was twice as likely to occur in births to multiparous teenage mothers in a low-income municipality, compared with those of older primiparous mothers in a wealthier municipality. Conclusions Socioeconomic factors substantially influence whether births of 22–24 weeks’ GA survive delivery and the first hour of life. Such disparities may reflect the impact of socioeconomic situations on decision making for resuscitation.

Survival in very preterm infants: an international comparison of 10 National Neonatal Networks

In this article, we compare the survival of very preterm infants in 10 national neonatal networks, showing marked differences in survival and age at death. OBJECTIVES: To compare survival rates and age at death among very preterm infants in 10 national and regional neonatal networks. METHODS: A cohort study of very preterm infants, born between 24 and 29 weeks’ gestation and weighing <1500 g, admitted to participating neonatal units between 2007 and 2013 in the International Network for Evaluating Outcomes of Neonates. Survival was compared by using standardized ratios (SRs) comparing survival in each network to the survival estimate of the whole population. RESULTS: Network populations differed with respect to rates of cesarean birth, exposure to antenatal steroids and birth in nontertiary hospitals. Network SRs for survival were highest in Japan (SR: 1.10; 99% confidence interval: 1.08–1.13) and lowest in Spain (SR: 0.88; 99% confidence interval: 0.85–0.90). The overall survival differed from 78% to 93% among networks, the difference being highest at 24 weeks’ gestation (range 35%–84%). Survival rates increased and differences between networks diminished with increasing gestational age (GA) (range 92%–98% at 29 weeks’ gestation); yet, relative differences in survival followed a similar pattern at all GAs. The median age at death varied from 4 days to 13 days across networks. CONCLUSIONS: The network ranking of survival rates for very preterm infants remained largely unchanged as GA increased; however, survival rates showed marked variations at lower GAs. The median age at death also varied among networks. These findings warrant further assessment of the representativeness of the study populations, organization of perinatal services, national guidelines, philosophy of care at extreme GAs, and resources used for decision-making.

Respiratory Management of Extremely Preterm Infants: An International Survey

Background: There are significant international variations in chronic lung disease rates among very preterm infants yet there is little data on international variations in respiratory strategies. Objective: To evaluate practice variations in the respiratory management of extremely preterm infants born at < 29 weeks’ gestational age (GA) among 10 neonatal networks participating in the International Network for Evaluating Outcomes (iNeo) of Neonates collaboration. Methods: A web-based survey was sent to the representatives of 390 neonatal intensive care units from Australia/New Zealand, Canada, Finland, Illinois (USA), Israel, Japan, Spain, Sweden, Switzerland, and Tuscany (Italy). Responses were based on practices in 2015. Results: Overall, 321 of the 390 units responded (82%). The majority of units within networks (40–92%) mechanically ventilate infants born at 23–24 weeks’ GA on continuous positive airway pressure (CPAP) with 30–39% oxygen in respiratory distress within 48 h after birth, but the proportion of units that offer mechanical ventilation for infants born at 25–26 weeks’ GA at similar settings varied significantly (20–85% of units within networks). The most common respiratory strategy for infants born at 27–28 weeks’ GA on CPAP with 30–39% oxygen with respiratory distress within 48 h after birth used by units also varied significantly among networks: mechanical ventilation (0–60%), CPAP (3–82%), intubation and surfactant administration with immediate extubation (0–75%), and less invasive surfactant administration (0–68%). Conclusions: There are marked variations but also similarities in respiratory management of extremely preterm infants between networks. Further collaboration and exploration is needed to better understand the association of these variations in practice with pulmonary outcomes.

Variations in Oxygen Saturation Targeting, and Retinopathy of Prematurity Screening and Treatment Criteria in Neonatal Intensive Care Units: An International Survey

Background: Rates of retinopathy of prematurity (ROP) and ROP treatment vary between neonatal intensive care units (NICUs). Neonatal care practices, including oxygen saturation (SpO2) targets and criteria for the screening and treatment of ROP, are potential contributing factors to the variations. Objectives: To survey variations in SpO2 targets in 2015 (and whether there had been recent changes) and criteria for ROP screening and treatment across the networks of the International Network for Evaluating Outcomes in Neonates (iNeo). Methods: Online prepiloted questionnaires on treatment practices for preterm infants were sent to the directors of 390 NICUs in 10 collaborating iNeo networks. Nine questions were asked and the results were summarized and compared. Results: Overall, 329/390 (84%) NICUs responded, and a majority (60%) recently made changes in upper and lower SpO2 target limits, with the median set higher than previously by 2–3% in 8 of 10 networks. After the changes, fewer NICUs (15 vs. 28%) set an upper SpO2 target limit > 95% and fewer (3 vs. 5%) a lower limit < 85%. There were variations in ROP screening criteria, and only in the Swedish network did all NICUs follow a single guideline. The initial retinal examination was carried out by an ophthalmologist in all but 6 NICUs, and retinal photography was used in 20% but most commonly as an adjunct to indirect ophthalmoscopy. Conclusions: There is considerable variation in SpO2 targets and ROP screening and treatment criteria, both within networks and between countries.

Association of Maternal Diabetes With Neonatal Outcomes of Very Preterm and Very Low-Birth-Weight Infants: An International Cohort Study

Importance Diabetes in pregnancy is associated with a 2-times to 3-times higher rate of very preterm birth than in women without diabetes. Very preterm infants are at high risk of death and severe morbidity. The association of maternal diabetes with these risks is unclear. Objective To determine the associations between maternal diabetes and in-hospital mortality, as well as neonatal morbidity in very preterm infants with a birth weight of less than 1500 g. Design, Setting, Participants This retrospective cohort study was conducted at 7 national networks in high-income countries that are part of the International Neonatal Network for Evaluating Outcomes in Neonates and used prospectively collected data on 76 360 very preterm, singleton infants without malformations born between January 1, 2007, and December 31, 2015, at 24 to 31 weeks’ gestation with birth weights of less than 1500 g, 3280 (4.3%) of whom were born to diabetic mothers. Exposures Any type of diabetes during pregnancy. Main Outcomes and Measures The primary outcome was in-hospital mortality. The secondary outcomes were severe neonatal morbidities, including intraventricular hemorrhages of grade 3 to 4, cystic periventricular leukomalacia, retinopathy of prematurity needing treatment and bronchopulmonary dysplasia, and other morbidities, including respiratory distress, treated patent ductus arteriosus, and necrotizing enterocolitis. Odds ratios (ORs) with 95% confidence intervals were estimated, adjusted for potential confounders, and stratified by gestational age (GA), sex, and network. Results The mean (SD) birth weight of offspring born to mothers with diabetes was significantly higher at 1081 (262) g than in offspring born to mothers without diabetes (mean [SD] birth weight, 1027 [270] g). Mothers with diabetes were older and had more hypertensive disorders, antenatal steroid treatments, and deliveries by cesarean delivery than mothers without diabetes. Infants of mothers with diabetes were born at a later GA than infants of mothers without diabetes. In-hospital mortality (6.6% vs 8.3%) and the composite of mortality and severe morbidity (31.6% vs 40.6%) were lower in infants of mothers with diabetes. However, in adjusted analyses, no significant differences in in-hospital mortality (adjusted OR, 1.16 (95% CI, 0.97-1.39) or the composite of mortality and severe morbidity (adjusted OR, 0.99 (95% CI, 0.88-1.10) were observed. With few exceptions, outcomes of infants born to mothers with and without diabetes were similar regardless of infant sex, GA, or country of birth. Conclusions and Relevance In high-resource settings, maternal diabetes is not associated with an increased risk of in-hospital mortality or severe morbidity in very preterm infants with a birth weight of fewer than 1500 g.