Opportunities and Challenges of Prognostic Models for Extremely Preterm Infants

Predicting the short- and long-term outcomes of extremely preterm infants remains a challenge. Multivariable prognostic models might be valuable tools for clinicians, parents, and policymakers for providing accurate outcome estimates. In this perspective, we discuss the opportunities and challenges of using prognostic models in extremely preterm infants at population and individual levels. At a population level, these models could support the development of guidelines for decisions about treatment limits and may support policy processes such as benchmarking and resource allocation. At an individual level, these models may enhance prenatal counselling conversations by considering multiple variables and improving transparency about expected outcomes. Furthermore, they may improve consistency in projections shared with parents. For the development of prognostic models, we discuss important considerations such as predictor and outcome measure selection, clinical impact assessment, and generalizability. Lastly, future recommendations for developing and using prognostic models are suggested. Importantly, the purpose of a prognostic model should be clearly defined, and integrating these models into prenatal counselling requires thoughtful consideration.</p

Higher hydrocortisone dose increases bilirubin in hypopituitary patients- Results from an RCT

Background Bilirubin has anti-oxidative and anti-inflammatory properties, which may explain its proposed protective effects on the development of cardiometabolic disorders. Glucocorticoids affect heme oxygenase regulation in vitro, which plays a key role in bilirubin production. Effects of variations in glucocorticoid exposure on circulating bilirubin levels in humans are unknown. Here we tested whether a higher hydrocortisone replacement dose affects circulating bilirubin in hypopituitary patients. Materials and methods A randomized double-blind cross-over study (ClinicalTrials.gov, number NCT01546992) was performed in 47 patients with secondary adrenal failure [10-week exposure to a higher hydrocortisone dose (0.4-0.6 mg/kg body weight) vs. 10 weeks of a lower hydrocortisone dose (0.2-0.3 mg/kg body weight)]. Results Plasma total bilirubin was increased by 10% from 7 to 8 mu M in response to the higher hydrocortisone dose (P = 0.033). This effect was inversely related to age (P = 0.042), but was unaffected by sex, obesity and (replacement for) other hormonal insufficiencies. The higher hydrocortisone dose also resulted in lower alkaline phosphatase (P = 0.006) and aspartate aminotransferase activities (P = 0.001). Conclusion Bilirubin is modestly increased in response to higher glucocorticoid exposure in humans, in conjunction with lower alkaline phosphatase and aspartate aminotransferase activities, which are supposed to represent biomarkers of a pro-inflammatory state and enhanced liver fat accumulation

Two-year neurodevelopmental outcome in children born extremely preterm:the EPI-DAF study

OBJECTIVE: In 2010, the Dutch practice regarding initiation of active treatment in extremely preterm infants was lowered from 25 completed weeks' to 24 completed weeks' gestation. The nationwide Extremely Preterm Infants - Dutch Analysis on Follow-up Study was set up to provide up-to-date data on neurodevelopmental outcome at 2 years' corrected age (CA) after this guideline change. Design: National cohort study. PATIENTS: All live born infants between 240/7 weeks' and 266/7 weeks' gestational age who were 2 years' CA in 2018-2020. MAIN OUTCOME MEASURE: Impairment at 2 years' CA, based on cognitive score (Bayley-III-NL), neurological examination and neurosensory function. RESULTS: 651 of 991 live born infants (66%) survived to 2 years' CA, with data available for 554 (85%). Overall, 62% had no impairment, 29% mild impairment and 9% moderate-to-severe impairment (further defined as neurodevelopmental impairment, NDI). The percentage of survivors with NDI was comparable for infants born at 24 weeks', 25 weeks' and 26 weeks' gestation. After multivariable analysis, severe brain injury and low maternal education were associated with higher odds on NDI. NDI-free survival was 48%, 67% and 75% in neonatal intensive care unit (NICU)-admitted infants at 24, 25 and 26 weeks' gestation, respectively. CONCLUSIONS: Lowering the threshold has not been accompanied by a large increase in moderate-to-severely impaired infants. Among live-born and NICU-admitted infants, an increase in NDI-free survival was observed from 24 weeks' to 26 weeks' gestation. This description of a national cohort with high follow-up rates gives an accurate description of the range of outcomes that may occur after extremely preterm birth

New insights into the kinetics and variability of egg excretion in controlled human hookworm infections

Four healthy volunteers were infected with 50 Necator americanus infective larvae (L3) in a controlled human hookworm infection trial and followed for 52 weeks. The kinetics of fecal egg counts in volunteers was assessed with Bayesian multilevel analysis, which revealed an increase between weeks 7 and 13, followed by an egg density plateau of about 1000 eggs/g of feces. Variation in egg counts was minimal between same-day measurements but varied considerably between days, particularly during the plateau phase. These analyses pave the way for the controlled human hookworm model to accelerate drug and vaccine efficacy studies

Two-year neurodevelopmental outcome in children born extremely preterm: the EPI-DAF study

OBJECTIVE: In 2010, the Dutch practice regarding initiation of active treatment in extremely preterm infants was lowered from 25 completed weeks' to 24 completed weeks' gestation. The nationwide Extremely Preterm Infants - Dutch Analysis on Follow-up Study was set up to provide up-to-date data on neurodevelopmental outcome at 2 years' corrected age (CA) after this guideline change. Design: National cohort study. PATIENTS: All live born infants between 24 0/7 weeks' and 26 6/7 weeks' gestational age who were 2 years' CA in 2018-2020. MAIN OUTCOME MEASURE: Impairment at 2 years' CA, based on cognitive score (Bayley-III-NL), neurological examination and neurosensory function. RESULTS: 651 of 991 live born infants (66%) survived to 2 years' CA, with data available for 554 (85%). Overall, 62% had no impairment, 29% mild impairment and 9% moderate-to-severe impairment (further defined as neurodevelopmental impairment, NDI). The percentage of survivors with NDI was comparable for infants born at 24 weeks', 25 weeks' and 26 weeks' gestation. After multivariable analysis, severe brain injury and low maternal education were associated with higher odds on NDI. NDI-free survival was 48%, 67% and 75% in neonatal intensive care unit (NICU)-admitted infants at 24, 25 and 26 weeks' gestation, respectively. CONCLUSIONS: Lowering the threshold has not been accompanied by a large increase in moderate-to-severely impaired infants. Among live-born and NICU-admitted infants, an increase in NDI-free survival was observed from 24 weeks' to 26 weeks' gestation. This description of a national cohort with high follow-up rates gives an accurate description of the range of outcomes that may occur after extremely preterm birth

Prognostic Models Predicting Mortality in Preterm Infants: Systematic Review and Meta-analysis

CONTEXT: Prediction models can be a valuable tool in performing risk assessment of mortality in preterm infants. OBJECTIVE: Summarizing prognostic models for predicting mortality in very preterm infants and assessing their quality. DATA SOURCES: Medline was searched for all articles (up to June 2020). STUDY SELECTION: All developed or externally validated prognostic models for mortality prediction in liveborn infants born <32 weeks' gestation and/or <1500 g birth weight were included. DATA EXTRACTION: Data were extracted by 2 independent authors. Risk of bias (ROB) and applicability assessment was performed by 2 independent authors using Prediction model Risk of Bias Assessment Tool. RESULTS: One hundred forty-two models from 35 studies reporting on model development and 112 models from 33 studies reporting on external validation were included. ROB assessment revealed high ROB in the majority of the models, most often because of inadequate (reporting of) analysis. Internal and external validation was lacking in 41% and 96% of these models. Meta-analyses revealed an average C-statistic of 0.88 (95% confidence interval [CI]: 0.83-0.91) for the Clinical Risk Index for Babies score, 0.87 (95% CI: 0.81-0.92) for the Clinical Risk Index for Babies II score, and 0.86 (95% CI: 0.78-0.92) for the Score for Neonatal Acute Physiology Perinatal Extension II score. LIMITATIONS: Occasionally, an external validation study was included, but not the development study, because studies developed in the presurfactant era or general NICU population were excluded. CONCLUSIONS: Instead of developing additional mortality prediction models for preterm infants, the emphasis should be shifted toward external validation and consecutive adaption of the existing prediction models

Prognostic models predicting mortality in preterm infants: Systematic review and meta-analysis

CONTEXT: Prediction models can be a valuable tool in performing risk assessment of mortality in preterm infants. OBJECTIVE: Summarizing prognostic models for predicting mortality in very preterm infants and assessing their quality. DATA SOURCES: Medline was searched for all articles (up to June 2020). STUDY SELECTION: All developed or externally validated prognostic models for mortality prediction in liveborn infants born ,32 weeks' gestation and/or ,1500 g birth weight were included. DATA EXTRACTION: Data were extracted by 2 independent authors. Risk of bias (ROB) and applicability assessment was performed by 2 independent authors using Prediction model Risk of Bias Assessment Tool. RESULTS: One hundred forty-two models from 35 studies reporting on model development and 112 models from 33 studies reporting on external validation were included. ROB assessment revealed high ROB in the majority of the models, most often because of inadequate (reporting of) analysis. Internal and external validation was lacking in 41% and 96% of these models. Meta-analyses revealed an average C-statistic of 0.88 (95% confidence interval [CI]: 0.83-0.91) for the Clinical Risk Index for Babies score, 0.87 (95% CI: 0.81-0.92) for the Clinical Risk Index for Babies II score, and 0.86 (95% CI: 0.78-0.92) for the Score for Neonatal Acute Physiology Perinatal Extension II score. LIMITATIONS: Occasionally, an external validation study was included, but not the development study, because studies developed in the presurfactant era or general NICU population were excluded. CONCLUSIONS: Instead of developing additional mortality prediction models for preterm infants, the emphasis should be shifted toward external validation and consecutive adaption of the existing prediction models

Ontwikkelingsproblemen bij vroeggeborenen

The French EPIPAGE-2 study evaluated a large group of premature born children (24-34 weeks' gestational age (GA))) at age 5.5 years. Outcome information of the whole cohort was presented after careful imputation including/using the variable socio-economic-status (SES), because participation rate improved with increasing SES. Survival improved with increasing GA. Survival without moderate or severe impairment was 20% in children born at 24-26 weeks' GA, but among the survivors 75% had no or mild impairment. Mild cognitive impairment rates were comparable and common among all GA groups (25-28%) and thus frequent in prematures. School problems were also common. In addition to prematurity, SES is an important risk factor for developmental impairment. Follow-up programs for premature infants beyond 30 weeks' GA are less common and may need extra attention in low SES families. Future studies should focus on both prevention of prematurity and programs to improve outcome

Developmental Trajectories in Very Preterm Born Children Up to 8 Years: A Longitudinal Cohort Study

Aim: Long-term outcome data in preterm children is often limited to cross-sectional measurement of neurodevelopmental impairment (NDI) at the corrected age of 24-36 months. However, impairments may only become overt during childhood or resolve with time, and individual trajectories in outcome over time may vary. The primary aim of this study was to describe NDI in very preterm born children at three subsequent ages of 2, 5, and 8 years of age. As a secondary aim, a longitudinal analysis was performed on the individual longitudinal trajectories in NDI from 2 to 8 years of age. Methods: Single-center prospective cohort study including children born between 1990 and 2011 below 30 weeks' gestation and followed into 2019. The outcome measurement was NDI assessed at 2, 5, and 8 years of age. NDI is a composite score that includes cognitive, neurological, visual, and auditory functions, in which problems were categorized as none, mild, moderate, or severe. Cognitive function measured as total DQ/IQ score was assessed by standardized psychometric tests. Neurological, visual, and auditory functions were assessed by the neonatologist. Results: In total, 921 children were eligible for follow-up, of whom 726 (79%) children were assessed. No NDI was seen in 54, 54, and 62%, mild NDI was seen in 31, 36, and 30%, and moderate-to-severe NDI was seen in 15, 9.2, and 8.6% of the children at 2, 5, and 8 years, respectively. From 2 to 8 years, 63% of the children remained in the same NDI category, 20% of the children improved to a better NDI category, and 17% deteriorated toward a worse NDI category. No differences were found in baseline characteristics of infants that improved or deteriorated. Extreme prematurity, male gender and low parental education were associated with worse NDI status at all time points. Although we observed considerable individual variation over time in NDI status, the course of the trajectories in NDI were not associated with gestation, gender, and parental education. Conclusions: Continued follow-up until school life is essential in order to provide optimal and individually focused referrals and care when needed