A recommendation for the use of electrical biosensing technology in neonatology.

Non-invasive cardiac output monitoring, via electrical biosensing technology (EBT), provides continuous, multi-parameter hemodynamic variable monitoring which may allow for timely identification of hemodynamic instability in some neonates, providing an opportunity for early intervention that may improve neonatal outcomes. EBT encompasses thoracic (TEBT) and whole body (WBEBT) methods. Despite the lack of relative accuracy of these technologies, as compared to transthoracic echocardiography, the use of these technologies in neonatology, both in the research and clinical arena, have increased dramatically over the last 30 years. The European Society of Pediatric Research Special Interest Group in Non-Invasive Cardiac Output Monitoring, a group of experienced neonatologists in the field of EBT, deemed it appropriate to provide recommendations for the use of TEBT and WBEBT in the field of neonatology. Although TEBT is not an accurate determinant of cardiac output or stroke volume, it may be useful for monitoring longitudinal changes of hemodynamic parameters. Few recommendations can be made for the use of TEBT in common neonatal clinical conditions. It is recommended not to use WBEBT to monitor cardiac output. The differences in technologies, study methodologies and data reporting should be addressed in ongoing research prior to introducing EBT into routine practice. IMPACT STATEMENT: TEBT is not recommended as an accurate determinant of cardiac output (CO) (or stroke volume (SV)). TEBT may be useful for monitoring longitudinal changes from baseline of hemodynamic parameters on an individual patient basis. TEBT-derived thoracic fluid content (TFC) longitudinal changes from baseline may be useful in monitoring progress in respiratory disorders and circulatory conditions affecting intrathoracic fluid volume. Currently there is insufficient evidence to make any recommendations regarding the use of WBEBT for CO monitoring in neonates. Further research is required in all areas prior to the implementation of these monitors into routine clinical practice.

Mind the gap: Comparing parents' information needs about impending preterm birth to current clinical practices using a mixed methods approach.

Objective: To identify parents' information needs about impending very preterm birth and compare these needs to current information practices in the Netherlands. Methods: Step 1: We surveyed N = 203 parents of preterm infants to assess their information needs. Data were analyzed using inductive thematic analysis. Step 2a: We collected information resources from hospitals (N = 9 NICUs) and via an online search. These materials were analyzed using deductive thematic analysis. Step 2b: We compared findings from Steps 1-2a. Results: We identified four themes pertaining to parents' information needs: (1) participation in care, (2) emotional wellbeing, (3) experience/success stories, and (4) practical information about prematurity. Clinicians' communicative skills and time were considered prerequisites for optimal information-provision. Notably, hospital resources provided mainly medical information about prematurity with some emphasis on participation in care, while parent associations mainly focused on emotional wellbeing and experience/success stories. Conclusion: While parents demonstrate clear information needs about impending very preterm birth, current information resources satisfy these partially. Innovation: Our multidisciplinary research team included both scholars and veteran NICU parents. As such, we identified parents' information needs bottom-up. These parent-driven insights will be used to design an innovative, tailored information platform for parents about impending very preterm birth.

Role of patent ductus arteriosus in preterms in long-term outcome.

OBJECTIVE: This study aimed to determine long-term neurodevelopmental outcome and cerebral oxygenation in extremely preterm infants, comparing those with a hemodynamic significant patent ductus arteriosus (hsPDA) to those without. STUDY DESIGN: We included infants born before 28 weeks of gestation from 2008 to 2010 with routine echocardiography. Prior to echocardiography, regional cerebral oxygen saturation was measured. At 5 years of age, we evaluated neurodevelopmental outcomes using the Movement Assessment Battery for Children 2nd Dutch edition for motor skills and the Wechsler Preschool and Primary Scale of Intelligence 3rd Dutch edition for cognition. RESULTS: A total of 66 infants (gestational age 26.6 ± 0.9 weeks, birth weight 912 ± 176 g) were included, 34 infants with a hsPDA (including treatment). The group infants with hsPDA showed lower pre-closure cerebral saturation levels (58.2 % ±7.8 % versus 62.8 % ±7.0 %; p = 0.01). At 5 years, impaired motor outcome occurred more often in infants with hsPDA (17 (53 %) vs. 7 (23 %); p = 0.01). In multivariate analysis existence of hsPDA remained unfavourably related to the motor subdomain "aiming and catching". There were no potential effects of hsPDA on cognitive performance at 5 years of age. CONCLUSION: Treatment-receiving infants with hsPDA appear to exhibit motor deficits, specifically in "aiming and catching", by the age 5. Persistent ductal patency could be a contributing factor.

Expectant Management or Early Ibuprofen for Patent Ductus Arteriosus.

BACKGROUND: Cyclooxygenase inhibitors are commonly used in infants with patent ductus arteriosus (PDA), but the benefit of these drugs is uncertain. METHODS: In this multicenter, noninferiority trial, we randomly assigned infants with echocardiographically confirmed PDA (diameter, >1.5 mm, with left-to-right shunting) who were extremely preterm (<28 weeks' gestational age) to receive either expectant management or early ibuprofen treatment. The composite primary outcome included necrotizing enterocolitis (Bell's stage IIa or higher), moderate to severe bronchopulmonary dysplasia, or death at 36 weeks' postmenstrual age. The noninferiority of expectant management as compared with early ibuprofen treatment was defined as an absolute risk difference with an upper boundary of the one-sided 95% confidence interval of less than 10 percentage points. RESULTS: A total of 273 infants underwent randomization. The median gestational age was 26 weeks, and the median birth weight was 845 g. A primary-outcome event occurred in 63 of 136 infants (46.3%) in the expectant-management group and in 87 of 137 (63.5%) in the early-ibuprofen group (absolute risk difference, -17.2 percentage points; upper boundary of the one-sided 95% confidence interval [CI], -7.4; P<0.001 for noninferiority). Necrotizing enterocolitis occurred in 24 of 136 infants (17.6%) in the expectant-management group and in 21 of 137 (15.3%) in the early-ibuprofen group (absolute risk difference, 2.3 percentage points; two-sided 95% CI, -6.5 to 11.1); bronchopulmonary dysplasia occurred in 39 of 117 infants (33.3%) and in 57 of 112 (50.9%), respectively (absolute risk difference, -17.6 percentage points; two-sided 95% CI, -30.2 to -5.0). Death occurred in 19 of 136 infants (14.0%) and in 25 of 137 (18.2%), respectively (absolute risk difference, -4.3 percentage points; two-sided 95% CI, -13.0 to 4.4). Rates of other adverse outcomes were similar in the two groups. CONCLUSIONS: Expectant management for PDA in extremely premature infants was noninferior to early ibuprofen treatment with respect to necrotizing enterocolitis, bronchopulmonary dysplasia, or death at 36 weeks' postmenstrual age. (Funded by the Netherlands Organization for Health Research and Development and the Belgian Health Care Knowledge Center; BeNeDuctus ClinicalTrials.gov number, NCT02884219; EudraCT number, 2017-001376-28.).

Obligately aerobic human gut microbe expresses an oxygen resistant tungsten-containing oxidoreductase for detoxifying gut aldehydes.

Brevibacillus massiliensis strain phR is an obligately aerobic microbe that was isolated from human feces. Here, we show that it readily takes up tungsten (W), a metal previously associated only with anaerobes. The W is incorporated into an oxidoreductase enzyme (BmWOR) that was purified from native biomass. BmWOR consists of a single 65 kDa subunit and contains a single W-pyranopterin cofactor and a single [4Fe-4S] cluster. It exhibited high aldehyde-oxidizing activity with very high affinities (apparent Km < 6 µM) for aldehydes common in the human gut and in cooked foods, including furfural, propionaldehyde, benzaldehyde and tolualdehyde, suggesting that BmWOR plays a key role in their detoxification. B. massiliensis converted added furfural to furoic acid when grown in the presence of W, but not in the presence of the analogous element molybdenum. B. massiliensis ferredoxin (BmFd) served as the electron acceptor (apparent Km < 5 µM) for BmWOR suggesting it is the physiological electron carrier. Genome analysis revealed a Fd-dependent rather than NADH-dependent Complex I, suggesting that WOR not only serves a detoxification role but its aldehyde substrates could also serve as a source of energy. BmWOR is the first tungstoenzyme and the first member of the WOR family to be obtained from a strictly aerobic microorganism. Remarkably, BmWOR oxidized furfural in the presence of air (21% O2, v/v) but only if BmFd was also present. BmWOR is the first characterized member of the Clade 83 WORs, which are predominantly found in extremely halophilic and aerobic archaea (Clade 83A), with many isolated from food sources, while the remaining bacterial members (Clade 83B) include both aerobes and anaerobes. The potential advantages for microbes found in foods and involved in human gut health that harbor O2-resistant WORs, including in Bacillus and Brevibacillus based-probiotics, are discussed.

Multi-centre, randomised non-inferiority trial of early treatment versus expectant management of patent ductus arteriosus in preterm infants (the BeNeDuctus trial): statistical analysis plan.

BACKGROUND: Controversy exists about the optimal management of a patent ductus arteriosus (PDA) in preterm infants. A persistent PDA is associated with neonatal mortality and morbidity, but causality remains unproven. Although both pharmacological and/or surgical treatment are effective in PDA closure, this has not resulted in an improved neonatal outcome. In most preterm infants, a PDA will eventually close spontaneously, hence PDA treatment potentially increases the risk of iatrogenic adverse effects. Therefore, expectant management is gaining interest, even in the absence of convincing evidence to support this strategy. METHODS/DESIGN: The BeNeDuctus trial is a multicentre, randomised, non-inferiority trial assessing early pharmacological treatment (24-72 h postnatal age) with ibuprofen versus expectant management of PDA in preterm infants in Europe. Preterm infants with a gestational age of less than 28 weeks and an echocardiographic-confirmed PDA with a transductal diameter of > 1.5 mm are randomly allocated to early pharmacological treatment with ibuprofen or expectant management after parental informed consent. The primary outcome measure is the composite outcome of mortality, and/or necrotizing enterocolitis Bell stage ≥ IIa, and/or bronchopulmonary dysplasia, all established at a postmenstrual age of 36 weeks. Secondary short-term outcomes are comorbidity and adverse events assessed during hospitalization and long-term neurodevelopmental outcome assessed at a corrected age of 2 years. This statistical analysis plan focusses on the short-term outcome and is written and submitted without knowledge of the data. TRIAL REGISTRATION: ClinicalTrials.gov NTR5479. Registered on October 19, 2015, with the Dutch Trial Registry, sponsored by the United States National Library of Medicine Clinicaltrials.gov NCT02884219 (registered May 2016) and the European Clinical Trials Database EudraCT 2017-001376-28.

Reducing medical device alarms by an order of magnitude: A human factors approach.

The intensive care unit (ICU) is one of the most technically advanced environments in healthcare, using a multitude of medical devices for drug administration, mechanical ventilation and patient monitoring. However, these technologies currently come with disadvantages, namely noise pollution, information overload and alarm fatigue-all caused by too many alarms. Individual medical devices currently generate alarms independently, without any coordination or prioritisation with other devices, leading to a cacophony where important alarms can be lost amongst trivial ones, occasionally with serious or even fatal consequences for patients. We have called this approach to the design of medical devices the single-device paradigm, and believe it is obsolete in modern hospitals where patients are typically connected to several devices simultaneously. Alarm rates of one alarm every four minutes for only the physiological monitors (as recorded in the ICUs of two hospitals contributing to this paper) degrades the quality of the patient's healing environment and threatens patient safety by constantly distracting healthcare professionals. We outline a new approach to medical device design involving the application of human factors principles which have been successful in eliminating alarm fatigue in commercial aviation. Our approach comprises the networked-device paradigm, comprehensive alarms and humaniform information displays. Instead of each medical device alarming separately at the patient's bedside, our proposed approach will integrate, prioritise and optimise alarms across all devices attached to each patient, display information more intuitively and hence increase alarm quality while reducing the number of alarms by an order of magnitude below current levels.

Helping Babies Breathe and its effects on intrapartum-related stillbirths and neonatal mortality in low-resource settings: a systematic review.

BACKGROUND: An important factor in worldwide neonatal mortality is the deficiency in neonatal resuscitation skills among trained professionals. 'Helping Babies Breathe' (HBB) is a simulation-based training course designed to train healthcare professionals in the initial steps of neonatal resuscitation in low-resource areas. The aim of this systematic review is to provide an overview of the available evidence regarding intrapartum-related stillbirths and neonatal mortality related to the HBB training and resuscitation method. DATA SOURCES: Cochrane, CINAHL, Embase, PubMed and Scopus. STUDY ELIGIBILITY CRITERIA: Conducted in low-resource settings focusing on the effects of HBB on intrapartum-related stillbirths and neonatal mortality. STUDY APPRAISAL: Included studies were reviewed independently by two researchers in terms of methodological quality. DATA EXTRACTION: Data were extracted by two independent reviewers and crosschecked by one additional reviewer. RESULTS: Seven studies were included in this systematic review; the selected studies included a total of 230.797 neonates. Significant decreases were found after the implementation of HBB in one of two studies describing perinatal mortality (n=25 108, rate ratio (RR) 0.75; p<0.001), four out of six studies related to intrapartum-related stillbirths (n=125.720, RR 0.31-0.76), in four out of five studies focusing on 1 day neonatal mortality (n=111.289, RR 0.37-0.67), and one out of three studies regarding 7 day neonatal mortality (n=4.390, RR 0.32). No changes were seen in late neonatal mortality after HBB training and resuscitation method. LIMITATIONS: Included studies in were predominantly of moderate quality, therefore no strong recommendations can be made. CONCLUSIONS AND IMPLICATIONS OF KEY FINDINGS: Due to the heterogeneous quality of the studies, this systematic review showed moderate evidence for a decrease in intrapartum-related stillbirth and 1-day neonatal mortality rate after implementing the 'Helping Babies Breathe' training and resuscitation method. Further research is required to address the effects of simulation-based team training on morbidity and mortality beyond the initial neonatal period. PROSPERO REGISTRATION NUMBER: CRD42018081141.

Early treatment versus expectative management of patent ductus arteriosus in preterm infants: a multicentre, randomised, non-inferiority trial in Europe (BeNeDuctus trial).

BACKGROUND: Much controversy exists about the optimal management of a patent ductus arteriosus (PDA) in preterm infants, especially in those born at a gestational age (GA) less than 28 weeks. No causal relationship has been proven between a (haemodynamically significant) PDA and neonatal complications related to pulmonary hyperperfusion and/or systemic hypoperfusion. Although studies show conflicting results, a common understanding is that medical or surgical treatment of a PDA does not seem to reduce the risk of major neonatal morbidities and mortality. As the PDA might have closed spontaneously, treated children are potentially exposed to iatrogenic adverse effects. A conservative approach is gaining interest worldwide, although convincing evidence to support its use is lacking. METHODS: This multicentre, randomised, non-inferiority trial is conducted in neonatal intensive care units. The study population consists of preterm infants (GA < 28 weeks) with an echocardiographic-confirmed PDA with a transductal diameter > 1.5 mm. Early treatment (between 24 and 72 h postnatal age) with the cyclooxygenase inhibitor (COXi) ibuprofen (IBU) is compared with an expectative management (no intervention intended to close a PDA). The primary outcome is the composite of mortality, and/or necrotising enterocolitis (NEC) Bell stage ≥ IIa, and/or bronchopulmonary dysplasia (BPD) defined as the need for supplemental oxygen, all at a postmenstrual age (PMA) of 36 weeks. Secondary outcome parameters are short term sequelae of cardiovascular failure, comorbidity and adverse events assessed during hospitalization and long-term neurodevelopmental outcome assessed at a corrected age of 2 years. Consequences regarding health economics are evaluated by cost effectiveness analysis and budget impact analysis. DISCUSSION: As a conservative approach is gaining interest, we investigate whether in preterm infants, born at a GA less than 28 weeks, with a PDA an expectative management is non-inferior to early treatment with IBU regarding to the composite outcome of mortality and/or NEC and/or BPD at a PMA of 36 weeks. TRIAL REGISTRATION: This trial is registered with the Dutch Trial Register NTR5479 (registered on 19 October 2015), the registry sponsored by the United States National Library of Medicine Clinicaltrials.gov NCT02884219 (registered May 2016) and the European Clinical Trials Database EudraCT 2017-001376-28 .

Cardiac Valve Annulus Diameters in Extremely Preterm Infants: A Cross-Sectional Echocardiographic Study.

BACKGROUND: With the increasing incidence of births of very preterm very-low-birth-weight infants, there is a demand for echocardiographic reference values of cardiac dimensions. OBJECTIVES: The aim of this study was to provide reference values of cardiac valve annulus diameters in a cohort of extremely preterm very-low-birth-weight neonates and to correlate these with patient characteristics. METHODS: Valve diameters of 376 infants of < 32 weeks' gestation and with a birth weight of ≤2,000 g were measured using 2-dimensional echocardiography. Correlations between valve diameters and patient characteristics (birth length/weight, body surface area, gestational age, and sex) were assessed. Birth weight was used to establish linear regression models. Inter- and intraobserver agreement was assessed through intraclass correlation coefficient (ICC) analysis. RESULTS: Substantial variability was found (aortic valve mean [standard deviation; range]: 5.0 mm [0.6; 3.7-6.5]; pulmonic valve: 5.8 mm [0.8; 3.4-7.9]; mitral valve: 8.0 mm [1.0; 5.5-10.5]; tricuspid valve: 7.6 mm [1.2; 4.9-10.6]). There was a moderate correlation between birth weight and valve diameter (R2 aortic valve: 0.36; pulmonic valve: 0.20; mitral valve: 0.24; tricuspid valve: 0.24). Adequate intraobserver (ICC range 0.74-0.91) and interobserver agreement (ICC range 0.77-0.89) was found. CONCLUSIONS: Our study provides ready-to-use reference values for cardiac valve annulus diameters for extremely preterm infants.

Primary coronary stent implantation is a feasible bridging therapy to surgery in very low birth weight infants with critical aortic coarctation.

BACKGROUND: Surgical treatment of critical aortic coarctation (CoA) is difficult in very low birth weight (VLBW) infants ≤1500 g and preferably postponed until 3 kg with prostaglandins (PGE). OBJECTIVES: To investigate the procedure and outcome of primary coronary stent implantation as bridging therapy to surgery in VLBW infants with CoA. METHODS: Retrospective evaluation of primary CoA stenting in VLBW infants from 2010 to 2015. RESULTS: Five VLBW infants with a median gestational age of 29 weeks (27-32) underwent primary CoA stenting. Indication was cardiac failure in 4 and severe hypertension in 1 patient. Age and weight at intervention were 14 days (range 12-16) and 1200 g (680-1380), respectively. Stent diameter ranged 3-5 mm. The femoral artery used for intervention was occluded in all infants without clinical compromise. Severe restenosis and aneurysm occurred in 1 VLBW infant and was successfully treated with covered coronary stents. Median age at surgical correction was 200 days (111-804) and weight 5500 g (4500-11,400). No reinterventions were required during a median postoperative follow-up of 2.8 years (0.1-5.0). Neurodevelopmental outcomes were normal and comparable between patients and siblings (4/5 gemelli). CONCLUSIONS: Primary coronary stent implantation in VLBW infants with critical CoA is a feasible bridging therapy to surgery.

Neonatal corticosteroid therapy affects growth patterns in early infancy.

OBJECTIVE: Although postnatal corticosteroid (CS) therapy has well established beneficial effects on pulmonary function, it may also result in growth restriction during treatment. The course of early childhood growth is believed to predict cardiovascular and metabolic diseases in adulthood. Therefore, we determined the effects of postnatal dexamethasone (DEX) or hydrocortisone (HC) treatment on patterns of postnatal growth until approximately four years of age. STUDY DESIGN: In an observational cohort study of children born prematurely (<32 weeks of gestation), we compared growth patterns for body weight, height, and head circumference from birth to age four years, of children who received DEX (boys: N = 30, girls: N = 14), HC (boys: N = 33, girls: N = 28) to a reference group that had not received postnatal CSs (boys: N = 52, girls: N = 53) using linear mixed-effects modeling. RESULTS: Growth velocity curves of CS-treated neonates showed a shift to the right, representing a delay in time. They had decreased absolute growth velocities during and shortly after treatment, followed by an increase in growth velocity thereafter. A shift to the right was also seen for the age at which maximal growth velocity of weight/height was reached in boys and girls. Fractional growth rates of weight, height, and head circumference were generally reduced in the CS-treated groups during the first two months of age, with catch-up growth in the following months. In DEX-treated infants these changes were more pronounced than in HC-treated infants. CONCLUSION: These data suggest that postnatal growth patterns of preterm born infants are affected by CS-treatment, more by DEX than by HC. Effects were observed mainly on growth velocities. This observation may have impact on health in later life for those individuals treated with CSs in the neonatal period. A definitive conclusion would require a randomized trial of these therapies.

Using benchmarking to identify inter-centre differences in persistent ductus arteriosus treatment: can we improve outcome?

OBJECTIVE: The aim of this study was to identify inter-centre differences in persistent ductus arteriosus treatment and their related outcomes. Materials and methods We carried out a retrospective, multicentre study including infants between 24+0 and 27+6 weeks of gestation in the period between 2010 and 2011. In all centres, echocardiography was used as the standard procedure to diagnose a patent ductus arteriosus and to document ductal closure. RESULTS: In total, 367 preterm infants were included. All four participating neonatal ICU had a comparable number of preterm infants; however, differences were observed in the incidence of treatment (33-63%), choice and dosing of medication (ibuprofen or indomethacin), number of pharmacological courses (1-4), and the need for surgical ligation after failure of pharmacological treatment (8-52%). Despite the differences in treatment, we found no difference in short-term morbidity between the centres. Adjusted mortality showed independent risk contribution of gestational age, birth weight, ductal ligation, and perinatal centre. CONCLUSIONS: Using benchmarking as a tool identified inter-centre differences. In these four perinatal centres, the factors that explained the differences in patent ductus arteriosus treatment are quite complex. Timing, choice of medication, and dosing are probably important determinants for successful patent ductus arteriosus closure.

Normative Values of Aortic Arch Structures in Premature Infants.

BACKGROUND: Aortic arch abnormalities represent 5% to 8% of all congenital heart disease. Measurements of the aortic arch dimensions on two-dimensional echocardiographic images remain of critical importance in the diagnosis of aortic arch pathology. To define aortic hypoplasia or coarctation, measured dimensions must be compared with normal values. Normal values have been described for children of all ages in earlier studies. However, normative data for premature infants are not yet available. Therefore, the aim of this study was to develop normative data in a cohort of premature infants, which could be used in the diagnosis of aortic arch abnormalities. METHODS: A single-center study was conducted in a large population of premature infants with gestational ages of ≤32 weeks without hemodynamically important congenital heart disease, chromosomal abnormalities, and/or major cerebral congenital malformations. Two-dimensional echocardiographic measurements of four aortic arch structures were made on the second, fourth, and sixth days after birth. RESULTS: Three hundred eighty-five preterm patients were included. No differences in dimensions were found among days 2, 4, and 6. The dimension of the isthmus showed no significant relation to the existence of a patent ductus arteriosus. Reference intervals with mean and SD were calculated across the range of birth weight. Regression analysis was performed with multiple determinants in different models. The best predictive value was found for birth weight in a cubic model. CONCLUSIONS: This work provides regression equations for the calculation of Z scores and reference intervals for aortic arch dimensions in a cohort of preterm infants born at gestational ages of ≤32 weeks. The normative data can be used in diagnosis and decision making involving aortic arch pathology in premature infants.

Cerebral oxygenation and echocardiographic parameters in preterm neonates with a patent ductus arteriosus: an observational study.

BACKGROUND: A haemodynamically significant patent ductus arteriosus (hsPDA) is clinically suspected and confirmed by echocardiographic examination. A hsPDA decreases cerebral blood flow and oxygen saturation by the ductal steal phenomenon. AIM: To determine the relationship between echocardiographic parameters, cerebral oxygenation and a hsPDA in preterm infants. METHODS: 380 preterm infants (<32 weeks gestational age) born between 2008 and 2010 were included. Blinded echocardiographic examination was performed on the second, fourth and sixth day after birth. Examinations were deblinded when hsPDA was clinically suspected. Regional cerebral oxygen saturation (rScO2) was continuously monitored by near-infrared spectroscopy during 72 h after birth, and afterwards for at least 1 h before echocardiography. Echocardiographic parameters included ductal diameter, end-diastolic flow in the left pulmonary artery, left atrium/aorta ratio and ductal flow pattern. RESULTS: rScO2 was significantly related only to ductal diameter over time. Mixed modelling analysed the course of rScO2 over time, where infants were divided into four groups: a closed duct, an open haemodynamically insignificant duct (non-sPDA), a hsPDA, which was successfully closed during study period (SC hsPDA) or a hsPDA, which was unsuccessfully closed during study period (UC hsPDA). SC hsPDA infants showed the highest rScO2 on day 6, while UC hsPDA infants had the lowest rScO2 values. CONCLUSIONS: Ductal diameter is the only echocardiographic parameter significantly related to cerebral oxygenation over time. Cerebral oxygenation takes a different course over time depending on the status of the duct. Low cerebral oxygenation may be suggestive of a hsPDA.

Neonatal glucocorticoid treatment: long-term effects on the hypothalamus-pituitary-adrenal axis, immune system, and problem behavior in 14-17 year old adolescents.

Neonatal glucocorticoid (GC) treatment is used to prevent bronchopulmonary dysplasia (BPD) in prematurely born babies. In the 1990s, treatment regimens with relatively high doses of dexamethasone (DEX) were common. As an alternative, hydrocortisone (HC) was used. Earlier, we compared long-term effects of both GCs in children aged 7-10 and detected adverse effects of neonatal DEX treatment, but not of HC, on a range of outcomes. The aim of the current cohort study was to investigate whether long-term effects of neonatal DEX were maintained and whether effects of HC remained absent at adolescent age (14-17years). We compared 71 DEX-treated and 67 HC-treated adolescents. In addition, 71 adolescents who were not neonatally treated with GCs participated. All were born <32weeks of gestation. DEX-treated girls showed increased adrenocorticotropic hormone (ACTH) and cortisol responses in the Trier Social Stress Test. The cortisol awakening response was lower in HC-treated participants compared to untreated participants. Negative feedback function of the HPA-axis in the dexamethasone suppression test did not differ between groups. In contrast to our observations at the age of 7-10years, we did not observe group differences in mitogen-induced cytokine production at the age of 14-17years. DEX-treated girls showed more social problems and anxious/depressed behavior than HC-treated girls. Untreated girls showed more problem behavior as well. In conclusion, our results suggest that, especially in girls, neonatal DEX has a programming effect on the HPA-axis and on the ability to adjust to the environment. The loss of group differences on immune system measures indicate that potentially negative effects detected at a younger age subsided.

Early detection of prenatal cardiocirculatory compromise in small for gestational age infants.

BACKGROUND: Impairment of gas and substrate exchange through the placenta leads to fetal hypoxia and growth restriction. Oxygenation of vital organs is maintained with preferential perfusion at the expense of less vital organs, challenging the fetal cardiovascular system. OBJECTIVES: To identify cardiovascular compromise in preterm small for gestational age (SGA) infants using the cardiac biomarker B-type natriuretic peptide (BNP), which indicates the workload of the myocardium. METHODS: In this retrospective case-control study, 26 SGA infants born at less than 32 weeks of gestation from October 2009 to October 2010 were matched for gestational age and month of birth with 26 appropriate for gestational age (AGA) infants. Antenatal Doppler ultrasound was used to identify fetal hemodynamic changes by determination of the pulsatility index (PI) of the middle cerebral artery (MCA-PI), umbilical artery (UA-PI) and veins of the ductus venosus (DV-PIV). These indices were compared with BNP levels obtained within 6 h after birth. RESULTS: Antenatal PIs of MCA, UA and DV were significantly related to elevated BNP levels after birth in SGA infants, but not in AGA infants (SGA: MCA-PI = r(2) 0.23, p < 0.05; UA-PI = r(2) 0.46, p < 0.01; DV-PIV = r(2) 0.31, p < 0.05). Furthermore, signs of perinatal (chronic) asphyxia coincided with elevated levels of BNP. SGA was related to more postnatal cardiocirculatory complications. No significant relations between postnatal cardiac ultrasound measurements, placenta size and BNP were found. CONCLUSION: BNP levels were elevated early after birth in SGA infants and corresponded positively with Doppler indices of circulatory compromise. This suggests an increased workload of the myocardium.

Antenatal glucocorticoid treatment affects hippocampal development in mice.

Synthetic glucocorticoids are administered to pregnant women at risk for preterm delivery, to enhance fetal lung maturation. The benefit of this treatment is well established, however caution is necessary because of possible unwanted side effects on development of different organ systems, including the brain. Actions of glucocorticoids are mediated by corticosteroid receptors, which are highly expressed in the hippocampus, a brain structure involved in cognitive functions. Therefore, we analyzed the effects of a single antenatal dexamethasone treatment on the development of the mouse hippocampus. A clinically relevant dose of dexamethasone (0.4 mg/kg) was administered to pregnant mice at embryonic day 15.5 and the hippocampus was analyzed from embryonic day 16 until adulthood. We investigated the effects of dexamethasone treatment on anatomical changes, apoptosis and proliferation in the hippocampus, hippocampal volume and on total body weight. Our results show that dexamethasone treatment reduced body weight and hippocampal volume transiently during development, but these effects were no longer detected at adulthood. Dexamethasone treatment increased the number of apoptotic cells in the hippocampus until birth, but postnatally no effects of dexamethasone treatment on apoptosis were found. During the phase with increased apoptosis, dexamethasone treatment reduced the number of proliferating cells in the subgranular zone of the dentate gyrus. The number of proliferative cells was increased at postnatal day 5 and 10, but was decreased again at the adult stage. This latter long-term and negative effect of antenatal dexamethasone treatment on the number of proliferative cells in the hippocampus may have important implications for hippocampal network function.

Statins prevent adverse effects of postnatal glucocorticoid therapy on the developing brain in rats.

BACKGROUND: Postnatal glucocorticoid therapy in the treatment of chronic lung disease benefits lung function, however it adversely affects brain development. We hypothesized that combined postnatal glucocorticoid and statin therapy diminishes adverse effects of glucocorticoids on the developing brain. METHODS: On postnatal days (P) 1-3, one male pup per litter received i.p. injections of saline control (C), n = 13) or dexamethasone (0.5, 0.3, 0.1 µg/g; D, n = 13), ± pravastatin (10 mg/kg i.p.; CP, n = 12; DP, n = 15). Statins or saline continued from P4-6. At P21, brains were perfusion fixed for histological and stereological analyses. RESULTS: Relative to controls, dexamethasone reduced total (837 ± 23 vs. 723 ± 37), cortical (378 ± 12 vs. 329 ± 15), and deep gray matter (329 ± 12 vs. 284 ± 15) volume (mm(3)), cortical neuronal number (23 ± 1 vs. 19 ± 1 × 10(6)), and hippocampal neuronal soma volume (CA1: 1,206 ± 32 vs. 999 ± 32; dentate gyrus: 679 ± 28 vs. 542 ± 24 µm(3); all P < 0.05). Dexamethasone increased the glial fibrillary acidic protein-positive astrocyte density in the white matter (96 ± 2 vs. 110 ± 4/0.1 mm(2)); P < 0.05. These effects no longer occurred in brains from pups treated with combined dexamethasone and pravastatin. Pravastatin alone had no effect on these variables. CONCLUSION: Concomitant dexamethasone with statins in premature infants may be safer for the developing brain than dexamethasone alone in the treatment of chronic lung disease.