Trends in neonatal morbidity and mortality for very low birthweight infants: a 20-year single-center experience.

OBJECTIVE: To describe trends in mortality and morbidity rates of very low birth weight infants as well as their pre-, peri- and postnatal characteristics over a period of 20 years' time. METHODS: Retrospective study in all very low birth weight infants admitted to the neonatal intensive care unit of the University Hospitals Ghent from 1 January 2000, to 31 December 2020. Mortality was the primary outcome variable with major morbidities being co-primary outcome variables. Pre-, peri- and postnatal characteristics are secondary outcome variables. We compared pre-, peri- and postnatal characteristics, as well as major morbidities between different groups with comparable rates of mortality. RESULTS: We included a total of 2037 very low birth weight infants and divided them in 3 epochs based on stepwise reductions in mortality in 2008 and 2013: 2000-2007 (n = 718), 2008-2012 (n = 506) and 2013-2020 (n = 813). Mortality decreased significantly over the years in all gestational ages, but predominantly in those with the youngest gestational age. Changes in obstetric and neonatal care were observed over time. Most significant changes were the increased use of antenatal corticosteroids, magnesium sulfate and surfactant. Intraventricular hemorrhage grade III/IV decreased significantly in all gestational ages. Significant increase in retinopathy of prematurity was observed. Bronchopulmonary dysplasia at 36 weeks and discharge home with oxygen is increasing in the total group. In those born below 26 weeks a slight increase in all major morbidities was observed especially of patent ductus arteriosus and retinopathy of prematurity. Increase of all other major morbidities seems to stabilize in epoch 3. The number of infants surviving without any major morbidity increases to almost 1/2 in all very low birth weight infants and to 1/10 in those born 24-25 weeks gestation. CONCLUSION: Analysis of the real-life experience showed that survival in very low birth weight infants significantly increased over time. Evolution of major morbidities will have to be carefully watched in the future.

Association of antenatal magnesium sulfate with reduced late-onset sepsis in extreme preterm infants.

OBJECTIVES: Neonatal intensive care has changed extensively over the last decades resulting in improved survival of extreme preterm infants. However, improved survival is associated with prolonged hospitalization, mechanical ventilation and use of invasive devices, which are all predisposing factors for LOS. LOS is known to increase short- and long-term morbidities resulting in impaired neurodevelopmental outcome. Besides treatment with antibiotics and supportive care, there is an unmet need for adjunctive therapies to prevent neonatal sepsis and hereby improve outcome. METHODS: In a retrospective single-center design, we explored underlying pre-, peri- and postnatal factors in extreme preterm infants with and without LOS to potentially identify future strategies in the prevention of LOS in these infants. RESULTS: Associations formerly published could be confirmed, such as lower birth weight, longer duration of respiratory support, parenteral nutrition and NICU stay and a higher incidence of almost all neonatal morbidities. A new interesting finding was the fact that infants with LOS received more antenatal magnesium sulfate (p = 0.002). After nearest neighbor matching based on birth weight, gestational age, gender and multiplicity increased duration of parenteral nutrition and NICU stay, the incidence of PVL remained significantly different between the two groups (LOS/no LOS), but also the association between antenatal magnesium sulfate administration and less LOS held true (p = 0.004). CONCLUSION: In this study, extreme preterm infants receiving antenatal magnesium sulfate developed less LOS. Whether this is merely an associative factor reflecting illness severity or an interesting link for new preventive strategies for LOS, should be further explored.

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.).

Intraparenchymal hemorrhage after serial ventricular reservoir taps in neonates with hydrocephalus and association with neurodevelopmental outcome at 2 years of age.

OBJECTIVE: Decompressing the ventricles with a temporary device is often the initial neurosurgical intervention for preterm infants with hydrocephalus. The authors observed a subgroup of infants who developed intraparenchymal hemorrhage (IPH) after serial ventricular reservoir taps and sought to describe the characteristics of IPH and its association with neurodevelopmental outcome. METHODS: In this multicenter, case-control study, for each neonate with periventricular and/or subcortical IPH, a gestational age-matched control with reservoir who did not develop IPH was selected. Digital cranial ultrasound (cUS) scans and term-equivalent age (TEA)-MRI (TEA-MRI) studies were assessed. Ventricular measurements were recorded prior to and 3 days and 7 days after reservoir insertion. Changes in ventricular volumes were calculated. Neurodevelopmental outcome was assessed at 2 years corrected age using standardized tests. RESULTS: Eighteen infants with IPH (mean gestational age 30.0 ± 4.3 weeks) and 18 matched controls were included. Reduction of the ventricular volumes relative to occipitofrontal head circumference after 7 days of reservoir taps was greater in infants with IPH (mean difference -0.19 [95% CI -0.37 to -0.004], p = 0.04). Cognitive and motor Z-scores were similar in infants with and those without IPH (mean difference 0.42 [95% CI -0.17 to 1.01] and 0.58 [95% CI -0.03 to 1.2]; p = 0.2 and 0.06, respectively). Multifocal IPH was negatively associated with cognitive score (coefficient -0.51 [95% CI -0.88 to -0.14], p = 0.009) and ventriculoperitoneal shunt with motor score (coefficient -0.50 [95% CI -1.6 to -0.14], p = 0.02) after adjusting for age at the time of assessment. CONCLUSIONS: This study reports for the first time that IPH can occur after a rapid reduction of the ventricular volume during the 1st week after the initiation of serial reservoir taps in neonates with hydrocephalus. Further studies on the use of cUS to guide the amount of cerebrospinal fluid removal are warranted.

Phenobarbital, Midazolam Pharmacokinetics, Effectiveness, and Drug-Drug Interaction in Asphyxiated Neonates Undergoing Therapeutic Hypothermia.

BACKGROUND: Phenobarbital and midazolam are commonly used drugs in (near-)term neonates treated with therapeutic hypothermia for hypoxic-ischaemic encephalopathy, for sedation, and/or as anti-epileptic drug. Phenobarbital is an inducer of cytochrome P450 (CYP) 3A, while midazolam is a CYP3A substrate. Therefore, co-treatment with phenobarbital might impact midazolam clearance. OBJECTIVES: To assess pharmacokinetics and clinical anti-epileptic effectiveness of phenobarbital and midazolam in asphyxiated neonates and to develop dosing guidelines. METHODS: Data were collected in the prospective multicentre PharmaCool study. In the present study, neonates treated with therapeutic hypothermia and receiving midazolam and/or phenobarbital were included. Plasma concentrations of phenobarbital and midazolam including its metabolites were determined in blood samples drawn on days 2-5 after birth. Pharmacokinetic analyses were performed using non-linear mixed effects modelling; clinical effectiveness was defined as no use of additional anti-epileptic drugs. RESULTS: Data were available from 113 (phenobarbital) and 118 (midazolam) neonates; 68 were treated with both medications. Only clearance of 1-hydroxy midazolam was influenced by hypothermia. Phenobarbital co-administration increased midazolam clearance by a factor 2.3 (95% CI 1.9-2.9, p < 0.05). Anticonvulsant effectiveness was 65.5% for phenobarbital and 37.1% for add-on midazolam. CONCLUSIONS: Therapeutic hypothermia does not influence clearance of phenobarbital or midazolam in (near-)term neonates with hypoxic-ischaemic encephalopathy. A phenobarbital dose of 30 mg/kg is advised to reach therapeutic concentrations. Phenobarbital co-administration significantly increased midazolam clearance. Should phenobarbital be substituted by non-CYP3A inducers as first-line anticonvulsant, a 50% lower midazolam maintenance dose might be appropriate to avoid excessive exposure during the first days after birth.

Pharmacokinetics of morphine in encephalopathic neonates treated with therapeutic hypothermia.

OBJECTIVE: Morphine is a commonly used drug in encephalopathic neonates treated with therapeutic hypothermia after perinatal asphyxia. Pharmacokinetics and optimal dosing of morphine in this population are largely unknown. The objective of this study was to describe pharmacokinetics of morphine and its metabolites morphine-3-glucuronide and morphine-6-glucuronide in encephalopathic neonates treated with therapeutic hypothermia and to develop pharmacokinetics based dosing guidelines for this population. STUDY DESIGN: Term and near-term encephalopathic neonates treated with therapeutic hypothermia and receiving morphine were included in two multicenter cohort studies between 2008-2010 (SHIVER) and 2010-2014 (PharmaCool). Data were collected during hypothermia and rewarming, including blood samples for quantification of morphine and its metabolites. Parental informed consent was obtained for all participants. RESULTS: 244 patients (GA mean (sd) 39.8 (1.6) weeks, BW mean (sd) 3,428 (613) g, male 61.5%) were included. Morphine clearance was reduced under hypothermia (33.5°C) by 6.89%/°C (95% CI 5.37%/°C- 8.41%/°C, p<0.001) and metabolite clearance by 4.91%/°C (95% CI 3.53%/°C- 6.22%/°C, p<0.001) compared to normothermia (36.5°C). Simulations showed that a loading dose of 50 µg/kg followed by continuous infusion of 5 µg/kg/h resulted in morphine plasma concentrations in the desired range (between 10 and 40 µg/L) during hypothermia. CONCLUSIONS: Clearance of morphine and its metabolites in neonates is affected by therapeutic hypothermia. The regimen suggested by the simulations will be sufficient in the majority of patients. However, due to the large interpatient variability a higher dose might be necessary in individual patients to achieve the desired effect. TRIAL REGISTRATION: www.trialregister.nl NTR2529.

Outcome of Infants with Therapeutic Hypothermia after Perinatal Asphyxia and Early-Onset Sepsis.

BACKGROUND: Animal models suggest that neuroprotective effects of therapeutic hypothermia (TH) after perinatal asphyxia are reduced in infants with early-onset sepsis. OBJECTIVES: To assess the outcome of infants with perinatal asphyxia, neonatal encephalopathy, and TH in the presence of early-onset sepsis. METHODS: In a retrospective cohort of 1,084 infants with perinatal asphyxia and TH, the outcome of 42 infants (gestational age 36.1-42.6 weeks and birth weight 2,280-5,240 g) with proven sepsis (n = 14) and probable sepsis (n = 28) was analyzed. Death, cerebral palsy, or a delayed development at 2 years was considered an adverse outcome. RESULTS: Sepsis was caused mostly by group B streptococci (n = 17), other Gram-positive bacteria (n = 5), and Candida albicans (n = 1). Of the 42 infants, 9 (21.4%) died, and 5 (11.9%) showed impairments on follow-up. The outcome is comparable to the previously reported outcome of infants with TH without early-onset sepsis. CONCLUSION: A good outcome was reported in the majority of infants with perinatal asphyxia, TH, and early-onset sepsis. Cooling should not be withheld from these infants.

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 .

Bedside Ultrasound-Guided Percutaneous Needle Aspiration of Intra- and Extra-Axial Intracranial Hemorrhage in Neonates.

Intracranial hemorrhage is an important cause of brain injury in the neonatal population and bedside percutaneous needle aspiration has emerged as an alternative due to the major risks that can be caused by standard neurosurgical decompression. We aimed to assess the effectiveness of this minimally invasive bedside technique and conducted a retrospective analysis of all newborn infants with a large extra-axial hemorrhage associated with a parenchymal hemorrhage causing a midline shift, managed at three academic centers over a 15-year period. Collected data included clinical history, laboratory results, review of all imaging studies performed, and neurodevelopmental follow-up. Eight infants (3 preterm and 5 full-term) presented on day 1 to 2 with seizures (n = 6) and apneas (n = 5), signs of increased intracranial pressure (n = 4), and coning (n = 1). Risk factors were present in six. Cranial ultrasound and computed tomography showed a midline shift in all; two infants showed status epilepticus on amplitude-integrated electroencephalography with complete resolution after the procedure. Between 7 and 34 mL could be aspirated associated with a decrease in the midline shift as seen by ultrasonography performed during the puncture. No complications were seen related to the procedure and none of the infants required further acute neurosurgical intervention. On follow-up, three had mild sequelae, including motor coordination problems (n = 1) and hemianopia (n = 2); none developed cerebral palsy or postneonatal epilepsy. Neonates, presenting with severe symptoms, can be managed successfully using ultrasound-guided needle aspiration and this minimally invasive bedside method should be kept in mind before performing neurosurgical decompression.

Evaluation of a System-Specific Function To Describe the Pharmacokinetics of Benzylpenicillin in Term Neonates Undergoing Moderate Hypothermia.

The pharmacokinetic (PK) properties of intravenous (i.v.) benzylpenicillin in term neonates undergoing moderate hypothermia after perinatal asphyxia were evaluated, as they have been unknown until now. A system-specific modeling approach was applied, in which our recently developed covariate model describing developmental and temperature-induced changes in amoxicillin clearance (CL) in the same patient study population was incorporated into a population PK model of benzylpenicillin with a priori birthweight (BW)-based allometric scaling. Pediatric population covariate models describing the developmental changes in drug elimination may constitute system-specific information and may therefore be incorporated into PK models of drugs cleared through the same pathway. The performance of this system-specific model was compared to that of a reference model. Furthermore, Monte-Carlo simulations were performed to evaluate the optimal dose. The system-specific model performed as well as the reference model. Significant correlations were found between CL and postnatal age (PNA), gestational age (GA), body temperature (TEMP), urine output (UO; system-specific model), and multiorgan failure (reference model). For a typical patient with a GA of 40 weeks, BW of 3,000 g, PNA of 2 days (TEMP, 33.5°C), and normal UO (2 ml/kg/h), benzylpenicillin CL was 0.48 liter/h (interindividual variability [IIV] of 49%) and the volume of distribution of the central compartment was 0.62 liter/kg (IIV of 53%) in the system-specific model. Based on simulations, we advise a benzylpenicillin i.v. dose regimen of 75,000 IU/kg/day every 8 h (q8h), 150,000 IU/kg/day q8h, and 200,000 IU/kg/day q6h for patients with GAs of 36 to 37 weeks, 38 to 41 weeks, and ≥42 weeks, respectively. The system-specific model may be used for other drugs cleared through the same pathway accelerating model development.

The Thompson Encephalopathy Score and Short-Term Outcomes in Asphyxiated Newborns Treated With Therapeutic Hypothermia.

BACKGROUND: The Thompson encephalopathy score is a clinical score to assess newborns suffering from perinatal asphyxia. Previous studies revealed a high sensitivity and specificity of the Thompson encephalopathy score for adverse outcomes (death or severe disability). Because the Thompson encephalopathy score was developed before the use of therapeutic hypothermia, its value was reassessed. OBJECTIVE: The purpose of this study was to assess the association of the Thompson encephalopathy score with adverse short-term outcomes, defined as death before discharge, development of severe epilepsy, or the presence of multiple organ failure in asphyxiated newborns undergoing therapeutic hypothermia. METHODS: The study period ranged from November 2010 to October 2014. A total of 12 tertiary neonatal intensive care units participated. Demographic and clinical data were collected from the "PharmaCool" multicenter study, an observational cohort study analyzing pharmacokinetics of medication during therapeutic hypothermia. With multiple logistic regression analyses the association of the Thompson encephalopathy scores with outcomes was studied. RESULTS: Data of 142 newborns were analyzed (male: 86; female: 56). Median Thompson score was 9 (interquartile range: 8 to 12). Median gestational age was 40 weeks (interquartile range 38 to 41), mean birth weight was 3362 grams (standard deviation: 605). All newborns manifested perinatal asphyxia and underwent therapeutic hypothermia. Death before discharge occurred in 23.9% and severe epilepsy in 21.1% of the cases. In total, 59.2% of the patients had multiple organ failure. The Thompson encephalopathy score was not associated with multiple organ failure, but a Thompson encephalopathy score ≥12 was associated with death before discharge (odds ratio: 3.9; confidence interval: 1.3 to 11.2) and with development of severe epilepsy (odds ratio: 8.4; confidence interval: 2.5 to 27.8). CONCLUSION: The Thompson encephalopathy score is a useful clinical tool, even in cooled asphyxiated newborns. A score ≥12 is associated with adverse outcomes (death before discharge and development of severe epilepsy). The Thompson encephalopathy score is not associated with the development of multiple organ failure.

Altered gentamicin pharmacokinetics in term neonates undergoing controlled hypothermia.

AIM(S): Little is known about the pharmacokinetic (PK) properties of gentamicin in newborns undergoing controlled hypothermia after suffering from hypoxic−ischaemic encephalopathy due to perinatal asphyxia. This study prospectively evaluates and describes the population PK of gentamicin in these patients METHODS: Demographic, clinical and laboratory data of patients included in a multicentre prospective observational cohort study (the 'PharmaCool Study') were collected. A non-linear mixed-effects regression analysis (nonmem®) was performed to describe the population PK of gentamicin. The most optimal dosing regimen was evaluated based on simulations of the final model. RESULTS: A total of 47 patients receiving gentamicin were included in the analysis. The PK were best described by an allometric two compartment model with gestational age (GA) as a covariate on clearance (CL). During hypothermia the CL of a typical patient (3 kg, GA 40 weeks, 2 days post-natal age (PNA)) was 0.06 l kg−1 h−1 (inter-individual variability (IIV) 26.6%) and volume of distribution of the central compartment (Vc) was 0.46 l kg−1 (IIV 40.8%). CL was constant during hypothermia and rewarming, but increased by 29% after reaching normothermia (>96 h PNA). CONCLUSIONS: This study describes the PK of gentamicin in neonates undergoing controlled hypothermia. The 29% higher CL in the normothermic phase compared with the preceding phases suggests a delay in normalization of CL after rewarming has occurred. Based on simulations we recommend an empiric dose of 5 mg kg−1 every 36 h or every 24 h for patients with GA 36­40 weeks and GA 42 weeks, respectively.

Introduction of hypothermia for neonates with perinatal asphyxia in the Netherlands and Flanders.

BACKGROUND: Therapeutic hypothermia was introduced in the Netherlands and Flanders, Belgium, in 2008. Since then, an increasing number of patients has been treated - up to 166 in 2010. Complications and outcome were registered in an online database. OBJECTIVES: The aim of this study was to analyse complications and outcome after implementation. METHODS: Data were retrieved from an online database to which all centres had contributed. RESULTS: In 3 years, 332 patients were treated. Excluding 24 patients with congenital abnormalities or metabolic disorders, mortality was 31.8%. Of the 210 survivors without congenital malformations, 21 had cerebral palsy, another 19 a developmental delay of more than 3 months at the age of at least 24 months, and 2 had severe hearing loss. The total adverse outcome, combining death and adverse neurodevelopment, in 308 patients without congenital malformations is 45.5%, which is similar to that of the large trials. CONCLUSIONS: The introduction of therapeutic hypothermia for neonates with perinatal asphyxia in the Netherlands and Flanders has been rapid and successful, with results similar to findings in the randomised controlled trials.

Effect of treatment of subclinical neonatal seizures detected with aEEG: randomized, controlled trial.

OBJECTIVES: The goals were to investigate how many subclinical seizures in full-term neonates with hypoxic-ischemic encephalopathy (HIE) would be missed without continuous amplitude-integrated electroencephalography (aEEG) and whether immediate treatment of both clinical and subclinical seizures would result in a reduction in the total duration of seizures and a decrease in brain injury, as seen on MRI scans. METHODS: In this multicenter, randomized, controlled trial, term infants with moderate to severe HIE and subclinical seizures were assigned randomly to either treatment of both clinical seizures and subclinical seizure patterns (group A) or blinding of the aEEG registration and treatment of clinical seizures only (group B). All recordings were reviewed with respect to the duration of seizure patterns and the use of antiepileptic drugs (AEDs). MRI scans were scored for the severity of brain injury. RESULTS: Nineteen infants in group A and 14 infants in group B were available for comparison. The median duration of seizure patterns in group A was 196 minutes, compared with 503 minutes in group B (not statistically significant). No significant differences in the number of AEDs were seen. Five infants in group B received AEDs when no seizure discharges were seen on aEEG traces. Six of 19 infants in group A and 7 of 14 infants in group B died during the neonatal period. A significant correlation between the duration of seizure patterns and the severity of brain injury in the blinded group, as well as in the whole group, was found. CONCLUSIONS: In this small group of infants with neonatal HIE and seizures, there was a trend for a reduction in seizure duration when clinical and subclinical seizures were treated. The severity of brain injury seen on MRI scans was associated with a longer duration of seizure patterns.

Lactic acidosis in a newborn with adrenal calcifications.

A patient is reported who presented in the newborn period with an unusual combination of congenital lactic acidosis and bilateral calcifications in the adrenal medulla, visible on standard abdominal x-ray and ultrasound examination. At birth, the proband was hypotonic and dystrophic. She developed respiratory insufficiency, cardiomegaly, and hepatomegaly and died at the age of 38 d. Examination of postmortem heart muscle revealed multiple areas of myocardial infarction with dystrophic calcifications. In the medulla of the adrenal glands, foci of necrosis and calcifications, and in the liver, multiple zones of necrosis and iron deposition were detected. Biochemical analysis in heart muscle revealed a decreased activity of complex IV of the oxidative phosphorylation (OXPHOS) and in liver a combined deficiency involving the complexes I, III, IV, and V. The findings were suggestive of a defect in biosynthesis of the mitochondrially encoded subunits of the OXPHOS complexes. Extensive analysis of the proband's mitochondrial DNA revealed neither pathogenic deletions and point mutations nor copy number alterations. Relative amounts of mitochondrial transcripts for the ribosomal mitochondrial 12S rRNA (12S) and mitochondrial 16S rRNA (16S) were significantly increased suggesting a compensatory mechanism involving the transcription machinery to low levels of translation. The underlying molecular defect has not been identified yet.

Imaging patterns of brain injury in term-birth asphyxia.

AIM: To develop an extended asphyxia-score based on cerebral ultrasound (US) and MRI in order to gain further insight into the pathophysiology of asphyxia. PATIENTS AND METHODS: First week cerebral US and MRI of 80 asphyxiated term infants were scored according to a new scoring system based on separate grading of injury to deep grey matter and to (sub)cortical/white matter. Our findings were compared with published scoring systems. RESULTS: Six patterns of brain injury were derived: deep grey matter injury with either limited or extensive cortical involvement, damage to deep grey matter with watershed injury, isolated watershed injury, isolated white matter injury (leukomalacia) and isolated cortical necrosis. The mortality rate was considerable in patterns with extensive cortical injury. CONCLUSION: Six patterns of brain injury, following term-birth asphyxia were found using a new imaging score.

Network injury to pulvinar with neonatal arterial ischemic stroke.

The purpose of this study is to establish that newborn stroke involving extensive parts of cerebral cortex immediately leads to secondary network injury in pulvinar. Seven term infants with cortical stroke presented with hypersignal in pulvinar on DWI. Stroke types included: complete MCA stroke (n=4); PCA stroke, ICA stroke and multiple artery stroke (1 each). Age range at scanning was between day 2 and 6 after birth (except for 1 infant scanned within 7 days of acute presentation during ECMO). ADC values in secondarily injured pulvinar were significantly higher than in the area with primary (sub)cortical injury (all patients scanned with identical MR image acquisition). In the absence of asphyxia and because pulvinar is outside of the primary area of infarction, we conclude that there are suggestions from imaging for acute secondary injury to pulvinar following primary damage of their cortical targets and/or connecting axons. Acute secondary injury is probably due to excitotoxicity and deafferentiation. The relevance of network injury for prognosis and the impact of early treatment on it have yet to be studied, in stroke but also in other acute perinatal brain disorders.

Evidence for autosomal dominant inheritance in prenatally diagnosed CHAOS.

Congenital high airway obstruction syndrome (CHAOS) is a rare prenatal diagnosis consisting of a typical fetal triad of large hyperechogenic lungs, flattened or inverted diaphragms and ascites. Most cases are sporadic with unknown incidence. Before attempts of fetoscopic fetal salvage or ex utero intrapartum treatment (EXIT) are considered, additional malformations must be carefully excluded as CHAOS may be part of various monogenic conditions or chromosomal disorders. We report an unique family with autosomal dominant inheritance of CHAOS and variable expression in the affected father and two affected children. It is concluded that minor expression in one of the parents may be an important indicator for genetic counseling in CHAOS and management of future pregnancies.

Phototherapy-mediated syndrome of inappropriate secretion of antidiuretic hormone in an in utero selective serotonin reuptake inhibitor-exposed newborn infant.

Although selective serotonin reuptake inhibitors (SSRIs) have gained wide acceptance in the off-label treatment of mental disorders in pregnant women, there seems to be an increased risk for serotonergic adverse effects in newborn infants who are exposed to SSRIs during late pregnancy. Hyponatremia as a result of the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) is a relatively common serious side effect of the use of SSRIs in (mostly elderly) adults. Severe hyponatremia as a result of an SIADH is proposed here as part of a neonatal serotonin toxicity syndrome in a newborn infant who was exposed prenatally to an SSRI. The definite reversal to normal serum sodium levels after fluid restriction, the lack of any alternative cause for the SIADH, and the positive temporal relation with a high score on a widely used adverse drug reaction probability scale offer solid support for the hypothesis of a causal relationship between the SIADH and the prenatal sertraline exposure in our neonate. Moreover, accumulative data on the acute enhancement of serotonergic transmission by intense illumination led us to hypothesize that phototherapy used to treat hyperbilirubinemia in the newborn infant could have been the ultimate environmental trigger for this proposed new cause of iatrogenic neonatal SIADH. The speculative role of phototherapy as a physical trigger for this drug-related adverse event should be confirmed in other cases by thorough study of the serotonin metabolism, assay of SSRI levels in cord blood, and serial measurement of plasma levels in exposed neonates. As phototherapy is used frequently in jaundiced neonates and an apparently increasing number of infants are born to mothers who take SSRIs, serotonin toxicity in neonates deserves increased attention.

Transplacental passage of a nonionic contrast agent.

UNLABELLED: We report the presence of iopromide in the bowel and urine of a preterm infant, born 10 days after intravenous administration of the nonionic monomer to his mother. Excessive urinary iodine excretion and borderline hyperthyrotropinaemia were observed in the infant. Moreover, crossing of the fetal blood-brain barrier was demonstrated by detection of the angiographic material in CSF and thus direct fetal neurotoxic effects cannot be excluded. CONCLUSION: These widely used contrast media may cross the placenta and accumulate in various fetal tissues in significant amounts causing possible neonatal toxicity. Therefore the perinatal safety of these diagnostic agents should at least be questioned.