Population pharmacokinetics of vancomycin in term neonates with perinatal asphyxia treated with therapeutic hypothermia.

AIMS: Little is known about the population pharmacokinetics (PPK) of vancomycin in neonates with perinatal asphyxia treated with therapeutic hypothermia (TH). We aimed to describe the PPK of vancomycin and propose an initial dosing regimen for the first 48 h of treatment with pharmacokinetic/pharmacodynamic target attainment. METHODS: Neonates with perinatal asphyxia treated with TH were included from birth until Day 6 in a multicentre prospective cohort study. A vancomycin PPK model was constructed using nonlinear mixed-effects modelling. The model was used to evaluate published dosing guidelines with regard to pharmacokinetic/pharmacodynamic target attainment. The area under the curve/minimal inhibitory concentration ratio of 400-600 mg*h/L was used as target range. RESULTS: Sixteen patients received vancomycin (median gestational age: 41 [range: 38-42] weeks, postnatal age: 4.4 [2.5-5.5] days, birth weight: 3.5 [2.3-4.7] kg), and 112 vancomycin plasma concentrations were available. Most samples (79%) were collected during the rewarming and normothermic phase, as vancomycin was rarely initiated during the hypothermic phase due to its nonempirical use. An allometrically scaled 1-compartment model showed the best fit. Vancomycin clearance was 0.17 L/h, lower than literature values for term neonates of 3.5 kg without perinatal asphyxia (range: 0.20-0.32 L/h). Volume of distribution was similar. Published dosing regimens led to overexposure within 24 h of treatment. A loading dose of 10 mg/kg followed by 24 mg/kg/day in 4 doses resulted in target attainment. CONCLUSION: Results of this study suggest that vancomycin clearance is reduced in term neonates with perinatal asphyxia treated with TH. Lower dosing regimens should be considered followed by model-informed precision dosing.

Association Between Seizures and Neurodevelopmental Outcome at Two and Five Years in Asphyxiated Newborns With Therapeutic Hypothermia.

OBJECTIVE: To investigate the association between the presence and severity of seizures in asphyxiated newborns and their neurodevelopmental outcome at ages two and five years. METHODS: Retrospective data analysis from a prospectively collected multicenter cohort of 186 term-born asphyxiated newborns undergoing therapeutic hypothermia (TH) in 11 centers in the Netherlands and Belgium. Seizures were diagnosed by amplitude-integrated electroencephalography (EEG) and raw EEG signal reading up to 48 hours after rewarming. Neurodevelopmental outcome was assessed by standardized testing at age two and five years. Primary outcome was death or long-term neurodevelopmental impairment (NDI) including cerebral palsy. Associations were calculated using univariate and multivariate logistic regression analyses adjusting for Thompson score and a validated brain magnetic resonance imaging (MRI) score. RESULTS: Seventy infants (38%) had seizures during TH or rewarming, and 44 (63%) of these needed two or more antiseizure medications (ASMs). Overall mortality was 21%. Follow-up data from 147 survivors were available for 137 infants (93%) at two and for 94 of 116 infants (81%) at five years. NDI was present in 26% at two and five years. Univariate analyses showed a significant association between seizures and death or NDI, but this was no longer significant after adjusting for Thompson and MRI score in the multivariate analysis; this was also true for severe seizures (need for two or more ASMs) or seizures starting during rewarming. CONCLUSION: The presence or severity of seizures in newborns undergoing TH for hypoxic-ischemic encephalopathy was not independently associated with death or NDI up to age five years after adjusting for several confounders.

Predictive Performance of a Gentamicin Pharmacokinetic Model in Term Neonates with Perinatal Asphyxia Undergoing Controlled Therapeutic Hypothermia.

BACKGROUND: Model validation procedures are crucial when population pharmacokinetic (PK) models are used to develop dosing algorithms and to perform model-informed precision dosing. We have previously published a population PK model describing the PK of gentamicin in term neonates with perinatal asphyxia during controlled therapeutic hypothermia (TH), which showed altered gentamicin clearance during the hypothermic phase dependent on gestational age and weight. In this study, the predictive performance and generalizability of this model were assessed using an independent data set of neonates with perinatal asphyxia undergoing controlled TH. METHODS: The external data set contained a subset of neonates included in the prospective observational multicenter PharmaCool Study. Predictive performance was assessed by visually inspecting observed-versus-predicted concentration plots and calculating bias and precision. In addition, simulation-based diagnostics, model refitting, and bootstrap analyses were performed. RESULTS: The external data set included 323 gentamicin concentrations of 39 neonates. Both the model-building and external data set included neonates from multiple centers. The original gentamicin PK model predicted the observed gentamicin concentrations with adequate accuracy and precision during all phases of controlled TH. Model appropriateness was confirmed with prediction-corrected visual predictive checks and normalized prediction distribution error analyses. Model refitting to the merged data set (n = 86 neonates with 935 samples) showed accurate estimation of PK parameters. CONCLUSIONS: The results of this external validation study justify the generalizability of the gentamicin dosing recommendations made in the original study for neonates with perinatal asphyxia undergoing controlled TH (5 mg/kg every 36 or 24 h with gestational age 36-41 and 42 wk, respectively) and its applicability in model-informed precision dosing.

Perioperative Brain Injury in Relation to Early Neurodevelopment Among Children with Severe Congenital Heart Disease: Results from a European Collaboration.

OBJECTIVE: To examine the relationship between perioperative brain injury and neurodevelopment during early childhood in patients with severe congenital heart disease (CHD). STUDY DESIGN: One hundred and seventy children with CHD and born at term who required cardiopulmonary bypass surgery in the first 6 weeks after birth were recruited from 3 European centers and underwent preoperative and postoperative brain MRIs. Uniform description of imaging findings was performed and an overall brain injury score was created, based on the sum of the worst preoperative or postoperative brain injury subscores. Motor and cognitive outcomes were assessed with the Bayley Scales of Infant and Toddler Development Third Edition at 12 to 30 months of age. The relationship between brain injury score and clinical outcome was assessed using multiple linear regression analysis, adjusting for CHD severity, length of hospital stay (LOS), socioeconomic status (SES), and age at follow-up. RESULTS: Neither the overall brain injury score nor any of the brain injury subscores correlated with motor or cognitive outcome. The number of preoperative white matter lesions was significantly associated with gross motor outcome after correction for multiple testing (P = .013, ß = -0.50). SES was independently associated with cognitive outcome (P < .001, ß = 0.26), and LOS with motor outcome (P < .001, ß = -0.35). CONCLUSION: Preoperative white matter lesions appear to be the most predictive MRI marker for adverse early childhood gross motor outcome in this large European cohort of infants with severe CHD. LOS as a marker of disease severity, and SES influence outcome and future intervention trials need to address these risk factors.

A Population Model of Time-Dependent Changes in Serum Creatinine in (Near)term Neonates with Hypoxic-Ischemic Encephalopathy During and After Therapeutic Hypothermia.

The objective was to apply a population model to describe the time course and variability of serum creatinine (sCr) in (near)term neonates with moderate to severe encephalopathy during and after therapeutic hypothermia (TH). The data consisted of sCr observations up to 10 days of postnatal age in neonates who underwent TH during the first 3 days after birth. Available covariates were birth weight (BWT), gestational age (GA), survival, and acute kidney injury (AKI). A previously published population model of sCr kinetics in neonates served as the base model. This model predicted not only sCr but also the glomerular filtration rate normalized by its value at birth (GFR/GFR0). The model was used to compare the TH neonates with a reference full term non-asphyxiated population of neonates. The estimates of the model parameters had good precision and showed high between subject variability. AKI influenced most of the estimated parameters denoting a strong impact on sCr kinetics and GFR. BWT and GA were not significant covariates. TH transiently increased [Formula: see text] in TH neonates over the first days compared to the reference group. Asphyxia impacted not only GFR, but also the [Formula: see text] synthesis rate. We also observed that AKI neonates exhibit a delayed onset of postnatal GFR increase and have a higher [Formula: see text] synthesis rate compared to no-AKI patients. Our findings show that the use of [Formula: see text] as marker of renal function in asphyxiated neonates treated with TH to guide dose selection for renally cleared drugs is challenging, while we captured the postnatal sCr patterns in this specific population.

Cranial MRI beyond the Neonatal Period and Neurodevelopmental Outcomes in Neonatal Encephalopathy Due to Perinatal Asphyxia: A Systematic Review.

BACKGROUND: Magnetic resonance imaging (MRI) including diffusion-weighted imaging within seven days after birth is widely used to obtain prognostic information in neonatal encephalopathy (NE) following perinatal asphyxia. Later MRI could be useful for infants without a neonatal MRI or in the case of clinical concerns during follow-up. Therefore, this review evaluates the association between cranial MRI beyond the neonatal period and neurodevelopmental outcomes following NE. METHODS: A systematic literature search was performed using PubMed and Embase on cranial MRI between 2 and 24 months after birth and neurodevelopmental outcomes following NE due to perinatal asphyxia. Two independent researchers performed the study selection and risk of bias analysis. Results were separately described for MRI before and after 18 months. RESULTS: Twelve studies were included (high-quality n = 2, moderate-quality n = 6, low-quality n = 4). All reported on MRI at 2-18 months: seven studies demonstrated a significant association between the pattern and/or severity of injury and overall neurodevelopmental outcomes and three showed a significant association with motor outcome. There were insufficient data on non-motor outcomes and the association between MRI at 18-24 months and neurodevelopmental outcomes. CONCLUSIONS: Cranial MRI performed between 2 and 18 months after birth is associated with neurodevelopmental outcomes in NE following perinatal asphyxia. However, more data on the association with non-motor outcomes are needed.

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.

Predictive performance of multiple organ dysfunction in asphyxiated newborns treated with therapeutic hypothermia on 24-month outcome: a cohort study.

BACKGROUND: Perinatal asphyxia may be followed by multiple organ dysfunction (MOD) and is often included in prognostication of the individual patient, but evidence of discriminating accuracy is lacking. The aim of this study was to assess whether MOD in asphyxiated neonates during therapeutic hypothermia (TH) predicts mortality or neurodevelopmental impairment (NDI) at 24 months of age and which peripartum variables are associated with the onset of MOD. METHODS: A retrospective analysis of a prospective cohort study of asphyxiated newborns undergoing TH was performed. MOD was defined as dysfunction of the brain (encephalopathy) combined with two or more organ systems. Outcome was routinely assessed by standardised developmental testing at the age of 24 months. The predictive accuracy of MOD on the combined outcome and its components (death and NDI) was expressed as areas under the receiver operating characteristic curves (AUROCs). The associations of peripartum variables and development of MOD were expressed as ORs and their CIs. RESULTS: 189 infants (median gestation 40 (range 36-42 weeks) with moderate to severe hypoxic ischaemic encephalopathy were included. 47% developed MOD. The prediction of the combined 24-month outcome or its components showed AUROCs <0.70. Associated with MOD were pH at birth (OR 0.97, CI 0.95 to 0.99), lactate at birth (OR 1.09, CI 1.04 to 1.15), Base Excess (BE) at birth (OR 0.94, CI 0.90 to 0.99) and epinephrine administration during resuscitation (OR 2.09, CI 1.02 to 4.40). CONCLUSION: MOD has a low discriminating accuracy in predicting mortality or NDI at 24 months age and might not be useful for prognostication. Signs of acid-base disturbance and adrenalin use at birth are associated with the development of MOD.

The Association of Dexamethasone and Hydrocortisone with Cerebellar Growth in Premature Infants.

OBJECTIVES: Corticosteroids are used to prevent or treat lung disease of prematurity. While neurological side effects have been reported, detailed effects on cerebellar growth are unknown. This study aimed to compare cerebellar growth in premature infants who received dexamethasone or hydrocortisone to premature infants who did not receive postnatal corticosteroids. STUDY DESIGN: Retrospective case-control study in infants born at a gestational age of <29 weeks and admitted to two level 3 neonatal intensive care units. Exclusion criteria were severe congenital anomalies and cerebellar or severe supratentorial lesions. Infants were treated with dexamethasone (unit 1) or hydrocortisone (unit 2) for chronic lung disease. Controls (unit 1) did not receive postnatal corticosteroids. Sequential head circumference (HC) and ultrasound measurements of transcerebellar diameter (TCD), biparietal diameter (BPD), and corpus callosum-fastigium length (CCFL) were performed until 40 weeks' postmenstrual age (PMA). Growth was assessed using linear mixed models correcting for PMA at measurement, sex, HC z-score at birth, and a propensity score indicating illness severity. Group differences before treatment were assessed using linear regression. RESULTS: 346 infants were included (68 dexamethasone, 37 hydrocortisone, 241 controls). Before starting corticosteroids, TCD, BPD, and HC measurements did not differ between patients and controls at a comparable PMA. After starting treatment, both types of corticosteroid had a negative association with TCD growth. BPD, CCFL, and HC growth were not negatively affected. CONCLUSION: Administration of dexamethasone and hydrocortisone are both associated with impaired cerebellar growth in premature infants without evident negative associations with cerebral growth.

Additional Value of 3-Month Cranial Magnetic Resonance Imaging in Infants with Neonatal Encephalopathy following Perinatal Asphyxia.

OBJECTIVE: To assess the evolution of neonatal brain injury noted on magnetic resonance imaging (MRI), develop a score to assess brain injury on 3-month MRI, and determine the association of 3-month MRI with neurodevelopmental outcome in neonatal encephalopathy (NE) following perinatal asphyxia. METHODS: This was a retrospective, single-center study including 63 infants with perinatal asphyxia and NE (n = 28 cooled) with cranial MRI <2 weeks and 2-4 months after birth. Both scans were assessed using biometrics, a validated injury score for neonatal MRI, and a new score for 3-month MRI, with a white matter (WM), deep gray matter (DGM), and cerebellum subscore. The evolution of brain lesions was assessed, and both scans were related to 18- to 24-month composite outcome. Adverse outcome included cerebral palsy, neurodevelopmental delay, hearing/visual impairment, and epilepsy. RESULTS: Neonatal DGM injury generally evolved into DGM atrophy and focal signal abnormalities, and WM/watershed injury evolved into WM and/or cortical atrophy. Although the neonatal total and DGM scores were associated with composite adverse outcomes, the 3-month DGM score (OR 1.5, 95% CI 1.2-2.0) and WM score (OR 1.1, 95% CI 1.0-1.3) also were associated with composite adverse outcomes (occurring in n = 23). The 3-month multivariable model (including the DGM and WM subscores) had higher positive (0.88 vs 0.83) but lower negative predictive value (0.83 vs 0.84) than neonatal MRI. Inter-rater agreement for the total, WM, and DGM 3-month score was 0.93, 0.86, and 0.59. CONCLUSIONS: In particular, DGM abnormalities on 3-month MRI, preceded by DGM abnormalities on the neonatal MRI, were associated with 18- to 24-month outcome, indicating the utility of 3-month MRI for treatment evaluation in neuroprotective trials. However, the clinical usefulness of 3-month MRI seems limited compared with neonatal MRI.

Population Pharmacokinetics and Dosing Optimization of Ceftazidime in Term Asphyxiated Neonates during Controlled Therapeutic Hypothermia.

Ceftazidime is an antibiotic commonly used to treat bacterial infections in term neonates undergoing controlled therapeutic hypothermia (TH) for hypoxic-ischemic encephalopathy after perinatal asphyxia. We aimed to describe the population pharmacokinetics (PK) of ceftazidime in asphyxiated neonates during hypothermia, rewarming, and normothermia and propose a population-based rational dosing regimen with optimal PK/pharmacodynamic (PD) target attainment. Data were collected in the PharmaCool prospective observational multicenter study. A population PK model was constructed, and the probability of target attainment (PTA) was assessed during all phases of controlled TH using targets of 100% of the time that the concentration in the blood exceeds the MIC (T>MIC) (for efficacy purposes and 100% T>4×MIC and 100% T>5×MIC to prevent resistance). A total of 35 patients with 338 ceftazidime concentrations were included. An allometrically scaled one-compartment model with postnatal age and body temperature as covariates on clearance was constructed. For a typical patient receiving the current dose of 100 mg/kg of body weight/day in 2 doses and assuming a worst-case MIC of 8 mg/L for Pseudomonas aeruginosa, the PTA was 99.7% for 100% T>MIC during hypothermia (33.7°C; postnatal age [PNA] of 2 days). The PTA decreased to 87.7% for 100% T>MIC during normothermia (36.7°C; PNA of 5 days). Therefore, a dosing regimen of 100 mg/kg/day in 2 doses during hypothermia and rewarming and 150 mg/kg/day in 3 doses during the following normothermic phase is advised. Higher-dosing regimens (150 mg/kg/day in 3 doses during hypothermia and 200 mg/kg/day in 4 doses during normothermia) could be considered when achievements of 100% T>4×MIC and 100% T>5×MIC are desired.

OPtimal TIming of antenatal COrticosteroid administration in pregnancies complicated by early-onset fetal growth REstriction (OPTICORE): study protocol of a multicentre, retrospective cohort study.

INTRODUCTION: Early-onset fetal growth restriction (FGR) requires timely, often preterm, delivery to prevent fetal hypoxia causing stillbirth or neurologic impairment. Antenatal corticosteroids (CCS) administration reduces neonatal morbidity and mortality following preterm birth, most effectively when administered within 1 week preceding delivery. Optimal timing of CCS administration is challenging in early-onset FGR, as the exact onset and course of fetal hypoxia are unpredictable. International guidelines do not provide a directive on this topic. In the Netherlands, two timing strategies are commonly practiced: administration of CCS when the umbilical artery shows (A) a pulsatility index above the 95thh centile and (B) absent or reversed end-diastolic velocity (a more progressed disease state). This study aims to (1) use practice variation to compare CCS timing strategies in early-onset FGR on fetal and neonatal outcomes and (2) develop a dynamic tool to predict the time interval in days until delivery, as a novel timing strategy for antenatal CCS in early-onset FGR. METHODS AND ANALYSIS: A multicentre, retrospective cohort study will be performed including pregnancies complicated by early-onset FGR in six tertiary hospitals in the Netherlands in the period between 2012 and 2021 (estimated sample size n=1800). Main exclusion criteria are multiple pregnancies and fetal congenital or genetic abnormalities. Routinely collected data will be extracted from medical charts. Primary outcome for the comparison of the two CCS timing strategies is a composite of perinatal, neonatal and in-hospital mortality. Secondary outcomes include the COSGROVE core outcome set for FGR. A multivariable, mixed-effects model will be used to compare timing strategies on study outcomes. Primary outcome for the dynamic prediction tool is 'days until birth'. ETHICS AND DISSEMINATION: The need for ethical approval was waived by the Ethics Committee (University Medical Center Utrecht). Results will be published in open-access, peer-reviewed journals and disseminated by presentations at scientific conferences. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov: NCT05606497.

Susceptibility weighted imaging can be a sensitive sequence to detect brain damage in neonates with kernicterus: a case report.

BACKGROUND: Kernicterus in the acute phase is difficult to diagnose. It depends on a high signal on T1 at the globus pallidum and subthalamic nucleus level. Unfortunately, these areas also show a relatively high signal on T1 in neonates as an expression of early myelination. Therefore, a less myelin-dependent sequence, like SWI, may be more sensitive to detecting damage in the globus pallidum area. CASE PRESENTATION: A term baby developed jaundice on day three following an uncomplicated pregnancy and delivery. Total bilirubin peaked at 542 µmol/L on day four. Phototherapy was started, and an exchange transfusion was performed. ABR showed absent responses on day 10. MRI on day eight demonstrated abnormal high signal globus pallidus on T1w, isointense on T2w, without diffusion restriction, and high signal on SWI at globus pallidal and subthalamus level and phase image at globus pallidal level. These findings were consistent with the challenging diagnosis of kernicterus. On follow-up, the infant presented with sensorineural hearing loss and had a work-up for cochlear implant surgery. At 3 months of age, the follow-up MR shows normalization of the T1 and SWI signals and a high signal on T2. CONCLUSIONS: SWI seems more sensitive to injury than the T1w and lacks the disadvantage of the T1w sequence, where early myelin confers a high signal.

Early predictors of neurodevelopment after perinatal arterial ischemic stroke: a systematic review and meta-analysis.

BACKGROUND AND AIMS: Perinatal arterial ischemic stroke (PAIS) often has lifelong neurodevelopmental consequences. We aimed to review early predictors (<4 months of age) of long-term outcome. METHODS: We carried out a systematic literature search (PubMed and Embase), and included articles describing term-born infants with PAIS that underwent a diagnostic procedure within four months of age, and had any reported outcome parameter ≥12 months of age. Two independent reviewers included studies and performed risk of bias analysis. RESULTS: We included 41 articles reporting on 1395 infants, whereof 1255 (90%) infants underwent follow-up at a median of 4 years. A meta-analysis was performed for the development of cerebral palsy (n = 23 studies); the best predictor was the qualitative or quantitative assessment of the corticospinal tracts on MRI, followed by standardized motor assessments. For long-term cognitive functioning, bedside techniques including (a)EEG and NIRS might be valuable. Injury to the optic radiation on DTI correctly predicted visual field defects. No predictors could be identified for behavior, language, and post-neonatal epilepsy. CONCLUSION: Corticospinal tract assessment on MRI and standardized motor assessments are best to predict cerebral palsy after PAIS. Future research should be focused on improving outcome prediction for non-motor outcomes. IMPACT: We present a systematic review of early predictors for various long-term outcome categories after perinatal arterial ischemic stroke (PAIS), including a meta-analysis for the outcome unilateral spastic cerebral palsy. Corticospinal tract assessment on MRI and standardized motor assessments are best to predict cerebral palsy after PAIS, while bedside techniques such as (a)EEG and NIRS might improve cognitive outcome prediction. Future research should be focused on improving outcome prediction for non-motor outcomes.

Delayed Surgical Closure of the Patent Ductus Arteriosus: Does the Brain Pay the Price?

OBJECTIVE: To investigate the relation between duration of hemodynamically significant patent ductus arteriosus (PDA), cerebral oxygenation, magnetic resonance imaging-determined brain growth, and 2-year neurodevelopmental outcome in a cohort of infants born preterm whose duct was closed surgically. STUDY DESIGN: Infants born preterm at <30 weeks of gestational age who underwent surgical ductal closure between 2008 and 2018 (n = 106) were included in this observational study. Near infrared spectroscopy-monitored cerebral oxygen saturation during and up to 24 hours after ductal closure and a Bayley III developmental test at the corrected age of 2 years is the institutional standard of care for this patient group. Infants also had magnetic resonance imaging at term-equivalent age. RESULTS: In total, 90 infants fulfilled the inclusion criteria (median [range]: 25.9 weeks [24.0-28.9]; 856 g [540-1350]. Days of a PDA ranged from 1 to 41. Multivariable linear regression analysis showed that duration of a PDA negatively influenced cerebellar growth and motor and cognitive outcome at 2 years of corrected age. CONCLUSIONS: Prolonged duration of a PDA in this surgical cohort is associated with reduced cerebellar growth and suboptimal neurodevelopmental outcome.

Normative mammillary body volumes: From the neonatal period to young adult.

The mammillary bodies may be small, but they have an important role in encoding complex memories. Mammillary body pathology often occurs following thiamine deficiency but there is increasing evidence that the mammillary bodies are also compromised in other neurological conditions and in younger ages groups. For example, the mammillary bodies are frequently affected in neonates with hypoxic-ischemic encephalopathy. At present, there is no normative data for the mammillary bodies in younger groups making it difficult to identify abnormalities in neurological disorders. To address this, the present study set out to develop a normative dataset for neonates and for children to young adult. A further aim was to determine whether there were laterality or sex differences in mammillary body volumes. Mammillary body volumes were obtained from MRI scans from 506 participants across two datasets. Measures for neonates were acquired from the Developing Human Connectome Project database (156 male; 100 female); volumes for individuals aged 6-24 were acquired from the NICHE database (166 males; 84 females). Volume measurements were acquired using a semi-automated multi-atlas segmentation approach. Mammillary body volumes increased up to approximately 15 years-of-age. The left mammillary body was marginally, but significantly, larger than the right in the neonates with a similar pattern in older children/young adults. In neonates, the mammillary bodies in males were slightly bigger than females but no sex differences were present in older children/young adults. Given the increasing presentation of mammillary body pathology in neonates and children, these normative data will enable better assessment of the mammillary bodies in healthy and at-risk populations.

Risk Factors for Perioperative Brain Lesions in Infants With Congenital Heart Disease: A European Collaboration.

BACKGROUND: Infants with congenital heart disease are at risk of brain injury and impaired neurodevelopment. The aim was to investigate risk factors for perioperative brain lesions in infants with congenital heart disease. METHODS: Infants with transposition of the great arteries, single ventricle physiology, and left ventricular outflow tract and/or aortic arch obstruction undergoing cardiac surgery <6 weeks after birth from 3 European cohorts (Utrecht, Zurich, and London) were combined. Brain lesions were scored on preoperative (transposition of the great arteries N=104; single ventricle physiology N=35; and left ventricular outflow tract and/or aortic arch obstruction N=41) and postoperative (transposition of the great arteries N=88; single ventricle physiology N=28; and left ventricular outflow tract and/or aortic arch obstruction N=30) magnetic resonance imaging for risk factor analysis of arterial ischemic stroke, cerebral sinus venous thrombosis, and white matter injury. RESULTS: Preoperatively, induced vaginal delivery (odds ratio [OR], 2.23 [95% CI, 1.06-4.70]) was associated with white matter injury and balloon atrial septostomy increased the risk of white matter injury (OR, 2.51 [95% CI, 1.23-5.20]) and arterial ischemic stroke (OR, 4.49 [95% CI, 1.20-21.49]). Postoperatively, younger postnatal age at surgery (OR, 1.18 [95% CI, 1.05-1.33]) and selective cerebral perfusion, particularly at ≤20 °C (OR, 13.46 [95% CI, 3.58-67.10]), were associated with new arterial ischemic stroke. Single ventricle physiology was associated with new white matter injury (OR, 2.88 [95% CI, 1.20-6.95]) and transposition of the great arteries with new cerebral sinus venous thrombosis (OR, 13.47 [95% CI, 2.28-95.66]). Delayed sternal closure (OR, 3.47 [95% CI, 1.08-13.06]) and lower intraoperative temperatures (OR, 1.22 [95% CI, 1.07-1.36]) also increased the risk of new cerebral sinus venous thrombosis. CONCLUSIONS: Delivery planning and surgery timing may be modifiable risk factors that allow personalized treatment to minimize the risk of perioperative brain injury in severe congenital heart disease. Further research is needed to optimize cerebral perfusion techniques for neonatal surgery and to confirm the relationship between cerebral sinus venous thrombosis and perioperative risk factors.