Impact of postnatal dexamethasone timing on preterm mortality and bronchopulmonary dysplasia: a propensity score analysis.

BACKGROUND: Postnatal dexamethasone (PND) is used in high-risk preterm infants after the first week of life to facilitate extubation and prevent bronchopulmonary dysplasia (BPD) but the optimal treatment timing remains unclear. Our objective was to explore the association between the timing of PND commencement and mortality and respiratory outcomes. METHODS: This was a retrospective National Neonatal Research Database study of 84 440 premature infants born <32 weeks gestational age from 2010 to 2020 in England and Wales. Propensity score weighting analysis was used to explore the impact of PND commenced at three time-points (2-3 weeks (PND2/3), 4-5 weeks (PND4/5) and after 5 weeks (PND6+) chronological age) on the primary composite outcome of death before neonatal discharge and/or severe BPD (defined as respiratory pressure support at 36 weeks) alongside other secondary respiratory outcomes. RESULTS: 3469 infants received PND. Compared with PND2/3, infants receiving PND6+ were more likely to die and/or develop severe BPD (OR 1.68, 95% CI 1.28-2.21), extubate at later postmenstrual age (mean difference 3.1 weeks, 95% CI 2.9-3.4 weeks), potentially require respiratory support at discharge (OR 1.34, 95% CI 1.06-1.70) but had lower mortality before discharge (OR 0.38, 95% CI 0.29-0.51). PND4/5 was not associated with severe BPD or discharge respiratory support. CONCLUSIONS: PND treatment after 5 weeks of age was associated with worse respiratory outcomes although residual bias cannot be excluded. A definitive clinical trial to determine the optimal PND treatment window, based on early objective measures to identify high-risk infants, is needed.

Observational cohort study of use of caffeine in preterm infants and association between early caffeine use and neonatal outcomes.

OBJECTIVE: To quantify trends in caffeine use in infants born at <32 weeks' gestational age (GA), and to investigate the effects of early vs late caffeine on neonatal outcomes. STUDY DESIGN: Retrospective propensity score matched cohort study using routinely recorded data from the National Neonatal Research Database of infants born at <32 weeks' GA admitted to neonatal units in England and Wales (2012-2020). RESULTS: 89% (58 913/66 081) of infants received caffeine. In 70%, caffeine was started early (on the day of birth or the day after), increasing from 55% in 2012 to 83% in 2020. Caffeine was given for a median (IQR) of 28 (17-43) days starting on day 2 (1-3) and continued up to 34 (33-34) weeks postmenstrual age.In the propensity score matched cohort of 13 045 pairs of infants, the odds of preterm brain injury (early caffeine, 2306/13 045 (17.7%) vs late caffeine, 2528/13 045 (19.4%), OR=0.89 (95% CI 0.84 to 0.95)) and bronchopulmonary dysplasia (BPD) (early caffeine, 4020/13 045 (32.8%) vs late caffeine, 4694/13 045 (37.7%), OR=0.81 (95% CI 0.76 to 0.85)) were lower in the group that received early caffeine compared with those who received it later. CONCLUSIONS: Early use of caffeine has increased in England and Wales. This is associated with reduced risks of BPD and preterm brain injury. Randomised trials are needed to find the optimal timing of caffeine use and the groups of infants who will benefit most from early administration of caffeine.

Bronchopulmonary dysplasia prediction models: a systematic review and meta-analysis with validation.

Prediction models could identify infants at the greatest risk of bronchopulmonary dysplasia (BPD) and allow targeted preventative strategies. We performed a systematic review and meta-analysis with external validation of identified models. Studies using predictors available before day 14 of life to predict BPD in very preterm infants were included. Two reviewers assessed 7628 studies for eligibility. Meta-analysis of externally validated models was followed by validation using 62,864 very preterm infants in England and Wales. A total of 64 studies using 53 prediction models were included totalling 274,407 infants (range 32-156,587/study). In all, 35 (55%) studies predated 2010; 39 (61%) were single-centre studies. A total of 97% of studies had a high risk of bias, especially in the analysis domain. Following meta-analysis of 22 BPD and 11 BPD/death composite externally validated models, Laughon's day one model was the most promising in predicting BPD and death (C-statistic 0.76 (95% CI 0.70-0.81) and good calibration). Six models were externally validated in our cohort with C-statistics between 0.70 and 0.90 but with poor calibration. Few BPD prediction models were developed with contemporary populations, underwent external validation, or had calibration and impact analyses. Contemporary, validated, and dynamic prediction models are needed for targeted preventative strategies. IMPACT: This review aims to provide a comprehensive assessment of all BPD prediction models developed to address the uncertainty of which model is sufficiently valid and generalisable for use in clinical practice and research. Published BPD prediction models are mostly outdated, single centre and lack external validation. Laughon's 2011 model is the most promising but more robust models, using contemporary data with external validation are needed to support better treatments.

Observational cohort study of changing trends in non-invasive ventilation in very preterm infants and associations with clinical outcomes.

OBJECTIVE: To determine the change in non-invasive ventilation (NIV) use over time in infants born at <32 weeks' gestation and the associated clinical outcomes. STUDY DESIGN: Retrospective cohort study using routinely recorded data from the National Neonatal Research Database of infants born at <32 weeks admitted to neonatal units in England and Wales from 2010 to 2017. RESULTS: In 56 537 infants, NIV use increased significantly between 2010 and 2017 (continuous positive airway pressure (CPAP) from 68.5% to 80.2% in 2017 and high flow nasal cannula (HFNC) from 14% to 68%, respectively) (p<0.001)). Use of NIV as the initial mode of respiratory support also increased (CPAP, 21.5%-28.0%; HFNC, 1%-7% (p<0.001)).HFNC was used earlier, and for longer, in those who received CPAP or mechanical ventilation. HFNC use was associated with decreased odds of death before discharge (adjusted OR (aOR) 0.19, 95% CI 0.17 to 0.22). Infants receiving CPAP but no HFNC died at an earlier median chronological age: CPAP group, 22 (IQR 10-39) days; HFNC group 40 (20-76) days (p<0.001). Among survivors, HFNC use was associated with increased odds of bronchopulmonary dysplasia (BPD) (aOR 2.98, 95% CI 2.81 to 3.15) and other adverse outcomes. CONCLUSIONS: NIV use is increasing, particularly as initial respiratory support. HFNC use has increased significantly with a sevenfold increase soon after birth which was associated with higher rates of BPD. As more infants survive with BPD, we need robust clinical evidence, to improve outcomes with the use of NIV as initial and ongoing respiratory support.

Education of family members to support weaning to solids and nutrition in later infancy in term-born infants.

BACKGROUND: Education of family members about infant weaning practices could affect nutrition, growth, and development of children in different settings across the world. OBJECTIVES: To compare effects of family nutrition educational interventions for infant weaning with conventional management on growth and neurodevelopment in childhood. SEARCH METHODS: We used the standard strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2018, Issue 5), MEDLINE via PubMed (1966 to 26 June 2018), Embase (1980 to 26 June 2018), and the Cumulative Index to Nursing and Allied Health Literature (CINAHL; 1982 to 26 June 2018). We searched clinical trials databases, conference proceedings, and references of retrieved articles. We ran an updated search from 1 January 2018 to 12 December 2019 in the following databases: CENTRAL via CRS Web, MEDLINE via Ovid, and CINAHL via EBSCOhost. SELECTION CRITERIA: We included randomised controlled trials that examined effects of nutrition education for weaning practices delivered to families of infants born at term compared to conventional management (standard care in the population) up to one year of age. DATA COLLECTION AND ANALYSIS: Two review authors independently identified eligible trial reports from the literature search and performed data extraction and quality assessments for each included trial. We synthesised effect estimates using risk ratios (RRs), risk differences (RDs), and mean differences (MDs), with 95% confidence intervals (CIs). We used the GRADE approach to assess the certainty of evidence. MAIN RESULTS: We included 21 trials, recruiting 14,241 infants. Five of the trials were conducted in high-income countries and the remaining 16 were conducted in middle- and low-income countries. Meta-analysis showed that nutrition education targeted at improving weaning-related feeding practices probably increases both weight-for-age z scores (WAZ) (MD 0.15 standard deviations, 95% CI 0.07 to 0.22; 6 studies; 2551 infants; I² = 32%; moderate-certainty evidence) and height-for-age z scores (0.12 standard deviations, 95% CI 0.05 to 0.19; 7 studies; 3620 infants; I² = 49%; moderate-certainty evidence) by 12 months of age. Meta-analysis of outcomes at 18 months of age was heterogeneous and inconsistent in the magnitude of effects of nutrition education on WAZ and weight-for-height z score across studies. One trial that assessed effects of nutrition education on growth at six years reported an uncertain effect on change in height and body mass index z score. Two studies investigated effects of nutrition education on neurodevelopment at 12 to 24 months of age with conflicting results. No trials assessed effects of nutrition education on long-term neurodevelopmental outcomes. AUTHORS' CONCLUSIONS: Nutrition education for families of infants may reduce the risk of undernutrition in term-born infants (evidence of low to moderate certainty due to limitations in study design and substantial heterogeneity of included studies). Modest effects on growth during infancy may not be of clinical significance. However, it is unclear whether these small improvements in growth parameters in the first two years of life affect long-term childhood growth and development. Further studies are needed to resolve this question.

Education of family members to support weaning to solids and nutrition in infants born preterm.

BACKGROUND: Weaning refers to the period of introduction of solid food to complement breast milk or formula milk. Preterm infants are known to acquire extrauterine growth restriction by the time of discharge from neonatal units. Hence, the postdischarge and weaning period are crucial for optimal growth. Optimisation of nutrition during weaning may have long-term impacts on outcomes in preterm infants. Family members of preterm infants may require nutrition education to promote ideal nutrition practices surrounding weaning in preterm infants who are at high risk of nutritional deficit. OBJECTIVES: To investigate the role of nutrition education of family members in supporting weaning in preterm infants with respect to their growth and neurodevelopment compared with conventional management. SEARCH METHODS: We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL 2018, Issue 5), MEDLINE via PubMed (1966 to 26 June 2018), Embase (1980 to 26 June 2018), and CINAHL (1982 to 26 June 2018). We also searched clinical trials databases, conference proceedings, and the reference lists of retrieved articles for randomised controlled trials (RCTs) and quasi-RCTs. SELECTION CRITERIA: RCTs and quasi-RCTs were eligible for inclusion if they examined the effects of nutrition education of family members as compared to conventional management for weaning of preterm infants up to one year of corrected gestational age. We defined prematurity as less than 37 completed weeks of gestation. DATA COLLECTION AND ANALYSIS: At least two review authors independently screened potential studies for inclusion and planned to identify, extract data, and assess the quality of eligible studies. We resolved any differences in opinion through discussion with a third review author and consensus among all three review authors. MAIN RESULTS: No eligible trials looking at the impact of nutrition education of family members in weaning of preterm infants fulfilled the inclusion criteria of this systematic review. Two studies investigating the ideal timing for weaning in premature infants reported conflicting results, AUTHORS' CONCLUSIONS: We were unable to assess the impact of nutrition education of family members in weaning of preterm infants as there were no eligible studies. This may be due to the lack of evidence to determine the ideal weaning strategies for preterm infants with regards to the time of initiating weaning and type of solids to introduce. Trials are needed to assess the many aspects of infant weaning in preterm infants. Long-term neurodevelopment and metabolic outcomes should also be assessed in addition to growth parameters.

Nicotine dependence and biochemical exposure measures in the second trimester of pregnancy.

INTRODUCTION: The Heaviness of Smoking Index (HSI) is validated to measure nicotine dependence in nonpregnant smokers, and in these smokers, mean salivary and serum cotinine levels are related by a ratio of 1.25. However, as nicotine metabolism increases during gestation, these findings may differ in pregnancy. We investigated the validity of HSI in pregnancy by comparing this with 3 biochemical measures; in a search for a less-invasive cotinine measure in pregnancy, we also explored the relationship between mean blood and salivary cotinine levels. METHODS: Cross-sectional analyses using baseline data from the Smoking, Nicotine, and Pregnancy Trial. Participants were 16-46 years old, 12-24 weeks gestation, smoked more than 5 cigarettes per day, and had exhaled carbon monoxide (CO) readings of at least 8 ppm. Linear regression was used to examine correlations between HSI and blood cotinine and salivary cotinine and exhaled CO. Correlation between blood and salivary cotinine was investigated using linear regression through the origin. RESULTS: HSI scores were associated with blood cotinine (R² = 0.20, n = 662, p < .001), salivary cotinine (R² = 0.11, n = 967, p < .001), and exhaled CO (R² = 0.13, n = 1,050, p < .001). Salivary and blood cotinine levels, taken simultaneously, were highly correlated (R² = 0.91, n = 628, p < .001) and the saliva:blood level ratio was 1.01 (95% CI 0.99-1.04). CONCLUSIONS: Correlations between HSI and biochemical measures in pregnancy were comparable with those obtained outside pregnancy, suggesting that HSI has similar validity in pregnant smokers. Salivary and blood cotinine levels are roughly equivalent in pregnant smokers.

Histological grading of breast cancer on needle core biopsy: the role of immunohistochemical assessment of proliferation.

AIMS: Histological grade assessed on needle core biopsy (NCB) moderately concurs with the grade in the surgical excision specimen (SES) (kappa-values between 0.35 and 0.65). A major cause of the discrepancy is underestimation of mitoses in the NCB specimen. The aim was to determine the best method of assessing proliferation on NCB. METHODS AND RESULTS: Proliferative activity of 101 invasive carcinomas of the breast on NCB and SES was assessed using mitotic counts on routine haematoxylin and eosin (H&E) sections and immunohistochemical markers Mib-1 and phosphorylated histone H3 (PPH3). H&E mitotic count in SES was considered as the gold standard. H&E mitotic count was found to be underestimated on NCB when compared with that in SES (P < 0.001), but no significant difference was detected between NCB and SES regarding Mib-1 (P = 0.13) or PPH3 (P = 0.073). Using receiver-operating characteristic curve, Mib-1 on NCB was found to agree with the gold standard significantly better than routine H&E on NCB. CONCLUSIONS: Immunohistochemical markers in NCB showed better concordance with H&E mitotic count in SES (gold standard) than routine H&E mitotic count in NCB. Further refinement of cut-offs and scoring methods is needed.