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.

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.

Neurodevelopmental outcome at 5.5 years in Dutch preterm infants born at 24-26 weeks' gestational age: the EPI-DAF study.

OBJECTIVE: After lowering the Dutch threshold for active treatment from 25 to 24 completed weeks' gestation, survival to discharge increased by 10% in extremely preterm live born infants. Now that this guideline has been implemented, an accurate description of neurodevelopmental outcome at school age is needed. DESIGN: Population-based cohort study. SETTING: All neonatal intensive care units in the Netherlands. PATIENTS: All infants born between 240/7 and 266/7 weeks' gestation who were 5.5 years' corrected age (CA) in 2018-2020 were included. MAIN OUTCOME MEASURES: Main outcome measure was neurodevelopmental outcome at 5.5 years. Neurodevelopmental outcome was a composite outcome defined as none, mild or moderate-to-severe impairment (further defined as neurodevelopmental impairment (NDI)), using corrected cognitive score (Wechsler Preschool and Primary Scale of Intelligence Scale-III-NL), neurological examination and neurosensory function. Additionally, motor score (Movement Assessment Battery for Children-2-NL) was assessed. All assessments were done as part of the nationwide, standardised follow-up programme. RESULTS: In the 3-year period, a total of 632 infants survived to 5.5 years' CA. Data were available for 484 infants (77%). At 5.5 years' CA, most cognitive and motor (sub)scales were significantly lower compared with the normative mean. Overall, 46% had no impairment, 36% had mild impairment and 18% had NDI. NDI-free survival was 30%, 49% and 67% in live born children at 24, 25 and 26 weeks' gestation, respectively (p<0.001). CONCLUSIONS: After lowering the threshold for supporting active treatment from 25 to 24 completed weeks' gestation, a considerable proportion of the surviving extremely preterm children did not have any impairment at 5.5 years' CA.

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.

Automated oxygen control for very preterm infants and neurodevelopmental outcome at 2 years-a retrospective cohort study.

Faster resolution of hypoxaemic or hyperoxaemic events in preterm infants may reduce long-term neurodevelopmental impairment. Automatic titration of inspiratory oxygen increases time within the oxygen saturation target range and may provide a more prompt response to hypoxic and hyperoxic events. We assessed routinely performed follow-up at 2 years of age after the implementation of automated oxygen control (AOC) as standard care and compared this with a historical cohort. Neurodevelopmental outcomes at 2 years of age were compared for infants born at 24-29 weeks gestational age before (2012-2015) and after (2015-2018) the implementation of AOC as standard of care. The primary outcome was a composite outcome of either mortality or severe neurodevelopmental impairment (NDI), and other outcomes assessed were mild-moderate NDI, Bayley-III composite scores, cerebral palsy GMFCS, and CBCL problem behaviour scores. A total of 289 infants were included in the pre-AOC epoch and 292 in the post-AOC epoch. Baseline characteristics were not significantly different. Fifty-one infants were lost to follow-up (pre-AOC 6.9% (20/289), post-implementation 10.6% (31/292). The composite outcome of mortality or severe NDI was observed in 17.9% pre-AOC (41/229) vs. 24.0% (47/196) post-AOC (p = 0.12). No significant differences were found for the secondary outcomes such as mild-moderate NDI, Bayley-III composite scores, cerebral palsy GMFCS, and problem behaviour scores, with the exception of parent-reported readmissions until the moment of follow-up which was less frequent post-AOC than pre-AOC. CONCLUSION: In this cohort study, the implementation of automated oxygen control in our NICU as standard of care for preterm infants led to no statistically significant difference in neurodevelopmental outcome at 2 years of age. WHAT IS KNOWN: • Neurodevelopmental outcome is linked to hypoxemia, hyperoxaemia and choice of SpO2 target range. • Automated titration of inspired oxygen may provide a faster resolution of hypoxaemic and hyperoxaemic events. WHAT IS NEW: • This cohort study did not find a significant difference in neurodevelopmental outcome at two years of age after implementing automated oxygen control as standard of care.

A longitudinal analysis of nosocomial bloodstream infections among preterm neonates.

Nosocomial bloodstream infections (NBSIs), commonly due to central-line associated bloodstream infections (CLABSI), contribute substantially to neonatal morbidity and mortality. We aimed to identify longitudinal changes in incidence of NBSI, microbiological-spectrum, and antibiotic exposure in a large cohort of preterm neonates admitted to the neonatal intensive care unit. We retrospectively assessed differences in annual rates of NBSI (per 1000 patient-days), CLABSI (per 1000 central-line days), and antibiotic consumption (per 1000 patient-days) among preterm neonates (< 32 weeks' gestation) hospitalized between January 2012 and December 2020. Multi-state Markov models were created to model states of progression of NBSI and infection risk given a central-line on days 0, 3, 7, and 10 of admission. Of 1547 preterm infants, 292 (19%) neonates acquired 310 NBSI episodes, 99 (32%) of which were attributed to a central-line. Over the years, a significant reduction in central-line use was observed (p < 0.001), although median dwell-time increased (p = 0.002). CLABSI incidence varied from 8.83 to 25.3 per 1000 central-line days, with no significant difference between years (p = 0.27). Coagulase-negative staphylococci accounted for 66% of infections. A significant decrease was found in antibiotic consumption (p < 0.001). Probability of NBSI decreased from 16% on day 3 to 6% on day 10. NBSI remains a common problem in preterm neonates. Overall antibiotic consumption decreased over time despite the absence of a significant reduction in infection rates. Further research aimed at reducing NBSI, in particular CLABSI, is warranted, particularly with regard to limiting central-line dwell-time and fine-tuning insertion and maintenance practices.

Social-emotional and behavioural issues after very preterm birth: Parental and teachers experiences.

Preterm infants are at risk of developing social-emotional and behavioural difficulties. To understand the experiences of their caregivers in day-to-day life, parents (at 2 and 10 years) and teachers (at 10 years) completed a behavioural questionnaire and answered two open-ended questions addressing their concerns and the most positive aspects regarding their child and/or pupil (born <32 weeks gestation). Their answers were analyzed using thematic content analysis. Parental concerns at two years related equally to themes in the clusters Developmental Milestones, Physical Development and Development in Relation to the Self and Others. At 10 years, both parents and teachers reported mainly within the cluster Development in Relation to the Self and Others, but the underlying themes differed. While parents more often mentioned their child's emotional development, teachers were more concerned about their pupils' difficulties interacting with their peers, due to a lack of social skills. In-depth qualitative analysis of what parents and teachers experience from day-to-day improves our understanding of the social-emotional and behavioural development of children born very preterm, revealing important topics that should be addressed during follow-up.

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

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

Persistent pulmonary hypertension in neonates with perinatal asphyxia and therapeutic hypothermia: a frequent and perilous combination.

OBJECTIVES: (1) To investigate whether neonates with perinatal asphyxia and therapeutic hypothermia more often developed PPHN compared to a control group with perinatal asphyxia not treated with hypothermia; (2) To identify risk factors for severe PPHN during hypothermia and evaluate short-term outcome. METHODS: This single-center retrospective cohort study included (near-)term neonates with perinatal asphyxia admitted between 2004 and 2016. Neonates with perinatal asphyxia and hypothermia were compared to a historical control group without hypothermia. Primary outcome was PPHN, defined as severe hypoxemia requiring mechanical ventilation and inhaled nitric oxide, confirmed by echocardiography. Short-term adverse outcome was defined as mortality within one month and/or severe brain injury on MRI. RESULTS: Incidence of PPHN was 23% (26/114) in the hypothermia group and 11% (8/70) in controls. In multivariate analysis, PPHN was 2.5 times more common among neonates with hypothermia. Neonates developing PPHN during hypothermia often had higher fraction of inspired oxygen at baseline. PPHN was not associated with a higher risk of severe brain injury. However, early mortality was higher and three infants died due to severe refractory PPHN during hypothermia. CONCLUSIONS: In this study PPHN occurred more often since the introduction of therapeutic hypothermia. This was usually reversible and did not lead to overall increased adverse outcome. However, in individual cases with PPHN deterioration occurred rapidly. In such cases the benefits of hypothermia should be weighed against the risk of a complicated, fatal course.

Neurodevelopmental Trajectories of Preterm Born Survivors of Twin-Twin Transfusion Syndrome: From Birth to 5 Years of Age.

OBJECTIVE: To investigate the neurodevelopmental outcome at age 2 and 5 years in survivors of twin-twin transfusion syndrome (TTTS) treated with fetoscopic laser surgery and born premature and/or small for gestational age. STUDY DESIGN: At 2 and 5 years of age, standardized neurologic, motor, and cognitive assessments were performed by a neonatologist, a pediatric physical therapist, and a psychologist. Behavior was assessed using a validated questionnaire completed by parents. RESULTS: Neurodevelopmental assessment at both time points was available for 73 survivors of TTTS. Mild to moderate neurodevelopmental impairment (NDI) was detected in 34% of survivors (25 of 73) at 5 years, compared with 25% (18 of 73) at 2 years (P = .178). Severe NDI was observed in 12% (9 of 73) at 5 years and in 3% (2 of 73) at 2 years (P = .035). Mean cognitive score was lower at the 5-year follow-up (90.7 ± 12.3 vs 95.6 ± 13.1 at 2 years; P = .001), and more children were diagnosed with mild cognitive impairment at 5 years (29% vs 11% at 2 years; P = .007). When comparing individual outcomes at both time points, 35% (25 of 71) moved from a normal outcome or mild to moderate impairment at 2 years toward more severe impairment at 5 years. CONCLUSIONS: A high rate of mild to moderate cognitive impairment and severe NDI at age 5 years was not identified at age 2 years. Our data highlight the importance of longitudinal follow-up of survivors of TTTS beyond age 2 years and emphasize the precautions that should be taken when diagnosing an absence of impairment before school age.

Outcome of non-cooled asphyxiated infants with under-recognised or delayed-onset encephalopathy.

OBJECTIVE: To describe the clinical characteristics, MRI findings and neurodevelopmental outcome of infants with documented perinatal asphyxia and seizure onset within 24 hours after birth who were not selected for therapeutic hypothermia (TH). DESIGN: Retrospective cohort study. SETTING AND PATIENTS: (Near-)term infants with documented perinatal asphyxia referred to two Dutch level III neonatal units with neonatal encephalopathy (NE) and seizures <24 hours after birth not treated with TH. Infants with a diagnosis other than NE following perinatal asphyxia causing the seizures were excluded. MAIN OUTCOME MEASURES: Clinical characteristics, findings on cranial MRI performed within 8 days after birth and neurodevelopmental outcome assessed using the Griffiths Mental Development Scales at 18 months or Bayley Scales of Infant and Toddler Development-Third Edition at 2 years of age. RESULTS: 39 infants were included. All had abnormalities on MRI. Predominant white matter/watershed injury was the most common pattern of injury, 23 (59%). 7 (18%) infants had predominant basal ganglia/thalamus injury, 3 (8%) near total brain injury, 5 (13%) arterial ischaemic stroke, 1 (3%) an intraventricular haemorrhage. Adverse outcome was seen in 51%: 6 died, 11 developed cerebral palsy (spastic n=8, dyskinetic n=3), 2 had neurodevelopmental delay, 1 had severe hearing impairment. CONCLUSIONS: All infants with documented perinatal asphyxia and seizure onset within 24 hours after birth who did not receive TH had abnormalities on MRI. 51% had an adverse outcome. Better methods for recognition of infants who might benefit from TH and careful neurodevelopmental follow-up are urgently needed.

Longitudinal Follow-Up of Children Born Preterm: Neurodevelopment From 2 to 10 Years of Age.

Objective: To investigate the rate and stability of impairments in children born preterm by assessing (1) early and school-age outcome in four developmental domains and (2) individual changes in outcome at both timepoints. Design: Prospective, longitudinal cohort study in children born in 2006-2007, <32 weeks' gestation. Follow-up at 2 and 10 years of age included standardized neurological, motor, cognitive and behavioral assessments. Children were categorized as having no, mild or moderate-severe impairment in these four domains. A composite impairment score was composed and the number of domains with impairments counted. For each child, individual outcomes at both timepoints were compared. Results: Follow-up at both time-points was available in 71/113(63%) children. At group level, there were no significant changes in the severity of impairments per domain. However, at individual level, there were less children with a mild abnormal composite score at 10 years of age (44 vs. 20%; p = 0.006), and more with a moderate-severe abnormal composite score (12 vs. 35%; p = 0.001). Especially children with normal/mild outcome at 2 years were likely to shift to other outcome categories over time. Conclusions: Children with early severe impairment are likely experiencing impairments later on, but early normal/mild abnormal outcomes should be interpreted with care, considering the large individual shifts over time. Long-term follow-up in all children born very preterm should therefore be continued to at least school-age.

Associations between Neonatal Magnetic Resonance Imaging and Short- and Long-Term Neurodevelopmental Outcomes in a Longitudinal Cohort of Very Preterm Children.

OBJECTIVE: To assess associations between neonatal brain injury assessed by magnetic resonance imaging and cognitive, motor, and behavioral outcomes at 2 and 10 years of age, in a longitudinal cohort of children born very preterm. STUDY DESIGN: There were 112 children born at <32 weeks of gestation who participated in a longitudinal prospective study on brain injury and neurodevelopmental outcome. Using the Kidokoro score, neonatal brain injury and altered brain growth in white matter, cortical and deep gray matter, and the cerebellum were assessed. Cognitive, motor, and behavioral outcomes were assessed during follow-up visits at both 2 (corrected) and 10 years of age. RESULTS: After adjusting for perinatal factors and level of maternal education, the global brain abnormality score was associated with cognition (B = -1.306; P = .005), motor skills (B = -3.176; P < .001), and behavior (B = 0.666; P = .005) at 2 years of age, but was not associated with cognition at 10 years of age. In the subgroup of children with a moderate-severe global brain abnormality score, magnetic resonance imaging was independently associated with cognitive impairment at 10 years of age. For children with milder forms of brain injury, only birth weight and level of maternal education were associated with cognitive outcomes. CONCLUSIONS: Neonatal brain injury, assessed by a standardized scoring system, was associated with short-term neurodevelopmental outcomes, but only with motor skills and behavior in childhood. Environmental factors, such as level of maternal education, become more important for cognitive development as children grow older, especially for children with relatively mild neonatal brain injury.

Behavioural outcome in twin-twin transfusion syndrome survivors treated with laser surgery.

OBJECTIVE: Evaluate the incidence of and risk factors for behavioural problems in twin-twin transfusion syndrome (TTTS) survivors treated with fetoscopic laser coagulation. DESIGN: Observational cohort study. SETTING: National referral center for fetal therapy, Leiden University Medical Center, The Netherlands. PATIENTS: Behavioural outcome was assessed in 417 TTTS survivors, at the age of 2 years. INTERVENTIONS: Parents completed the Child Behavior Checklist for their twins. Antenatal, neonatal and follow-up data including Bayley III and a neurological exam were recorded from the medical database. MAIN OUTCOME MEASURES: The incidence of and risk factors for behavioural problems. RESULTS: 332 twin pregnancies (664 fetuses) were treated with fetoscopic laser for TTTS between 2008 and 2015. For 517 children eligible for follow-up, 417 (81%) Child Behavior Checklist questionnaires were completed. The study group was born at a mean gestational age of 32.8 weeks±3.2. Total behavioural problems within the borderline to clinical range were reported in 8% (95% CI 5.9 to 11.2) of survivors, compared with 10% in the general Dutch population (p=0.12). No difference between donors and recipients was detected (p=0.84). Internalising and externalising problems were reported in 9.4% (95% CI 6.9 to 12.6) and 11.5% (95% CI 8.8 to 15.0), respectively. Severe neurodevelopmental impairment was more frequent in the children with behavioural problems. High maternal educational level was associated with lower behavioural problem scores. CONCLUSION: Parents of twins treated with fetoscopic laser therapy for TTTS do not report more behavioural problems compared with general population norms. More behavioural problems are reported in children with severe neurodevelopmental impairment.

Lidocaine as treatment for neonatal seizures: Evaluation of previously developed population pharmacokinetic models and dosing regimen.

AIMS: Lidocaine is used to treat neonatal seizures refractory to other anticonvulsants. It is effective, but also associated with cardiac toxicity. Previous studies have reported on the pharmacokinetics of lidocaine in preterm and term neonates and proposed a dosing regimen for effective and safe lidocaine use. The objective of this study was to evaluate the previously developed pharmacokinetic models and dosing regimen. As a secondary objective, lidocaine effectiveness and safety were assessed. METHODS: Data from preterm neonates and (near-)term neonates with and without therapeutic hypothermia receiving lidocaine were included. Pharmacokinetic analyses were performed using non-linear mixed effects modelling. Simulations were performed to evaluate the proposed dosing regimen. Lidocaine was considered effective if no additional anticonvulsant was required and safe if no cardiac adverse events occurred. RESULTS: Data were available for 159 neonates; 50 (31.4%) preterm and 109 term neonates, of whom 49 (30.8%) were treated with therapeutic hypothermia. Lidocaine clearance increased with postmenstrual age by 0.69%/day (95% confidence interval 0.54-0.84%). During therapeutic hypothermia (33.5°C), lidocaine clearance was reduced by 21.8% (7.26%/°C, 95% confidence interval 1.63-11.2%) compared to normothermia (36.5°C). Simulations demonstrated that the proposed dosing regimen leads to adequate average lidocaine plasma concentrations. Effectiveness and safety were assessed in 92 neonates. Overall effectiveness was 53.3% (49/92) and 56.5% (13/23) for neonates receiving the proposed dosing regimen. No cardiac toxicity was observed. CONCLUSION: Lidocaine pharmacokinetics was adequately described across the entire neonatal age range. With the proposed dosing regimen, lidocaine can provide effective and safe treatment for neonatal seizures.

Classroom-evaluated school performance at nine years of age after very preterm birth.

OBJECTIVE: To determine classroom-evaluated school performance nine years after preterm birth, predicted by perinatal risk factors and neonatal brain abnormalities. STUDY DESIGN: Children were recruited from a consecutive cohort of 113 preterm infants (<32 weeks' gestation), participating in a longitudinal prospective study, investigating brain injury and neurodevelopmental outcome. Data on perinatal risk factors, presence of brain injury at term-equivalent age, and maternal education were collected. Information on school performance included enrollment in special (primary) education, grade repetition and school results from the nationwide standardized Dutch Pupil Monitoring System regarding reading comprehension, spelling, and mathematics. RESULTS: Information on school enrollment was available for 87 children (77%), of whom 7 (8%) were in special primary education and 19 (22%) repeated a grade. This was significantly higher compared to national rates (p ≤ .05). Results on school performance were available for 74 children (65%) and showed clearly below average scores in reading comprehension (p = .006), spelling (p = .014) and mathematics (p < .001). Univariate analysis showed that lower performance in reading comprehension was predicted by male sex and low maternal education; spelling by male sex; and mathematics by Bronchopulmonary Dysplasia, white matter injury and maternal education. In a multivariate model, male sex and maternal education were predictive for reading comprehension and white matter injury for mathematics. CONCLUSION: Preterm born children more often need special primary education and have higher grade repeat rates. They perform poorer on reading comprehension, spelling and mathematics. Regular follow-up remains important for preterm born children during school age.

Long-Term Neurodevelopmental Outcome in Twin-to-Twin Transfusion Syndrome: Is there still Room for Improvement?

Despite many developments in its management, twin-to-twin transfusion syndrome (TTTS) remains an important risk factor for long-term neurodevelopmental impairment (NDI). Our objective was to compare the incidence of severe NDI in a recent cohort of TTTS survivors, treated with laser surgery from 2011 to 2014, with a previous cohort treated from 2008 to 2010. Neurological, cognitive, and motor development were assessed at two years of age. We determined risk factors associated with Bayley-III scores. Severe NDI occurred in 7/241 (3%) survivors in the new cohort compared to 10/169 (6%) in the previous cohort (p = 0.189). Disease-free survival (survival without severe impairment) did not significantly differ. Low birth weight and being small for gestational age (SGA) were independently associated with lower cognitive scores (both p < 0.01). Severe cerebral injury was related to decreased motor scores (B = -14.10; 95% CI -3.16, -25.04; p = 0.012). Children with severe NDI were born ≥32 weeks' gestation in 53% of cases and had no evidence of cerebral injury on cranial ultrasound in 59% of cases. Our results suggest that improvement in outcome of TTTS has reached a plateau. Low birth weight, SGA, and cerebral injury are risk factors for poor neurodevelopmental outcome. Neither gestational age above 32 weeks nor the absence of cerebral injury preclude severe NDI.

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.

Long-Term Neurodevelopmental and Respiratory Outcome after Intrauterine Therapy for Fetal Thoracic Abnormalities.

INTRODUCTION: The aim of this study is to evaluate long-term neurodevelopmental and respiratory outcome after fetal therapy for fetal pleural effusion, congenital cystic adenomatoid malformation, and bronchopulmonary sequestration. METHODS: Children ≥18 months of age underwent an assessment of neurologic, motor, and cognitive development. Medical records were reviewed to determine respiratory outcome. Behavioral outcome was assessed using the Child Behavioral Checklist. RESULTS: Between 2001 and 2016, 63 fetuses with fetal hydrops secondary to thoracic abnormalities were treated at our center. Overall perinatal survival was 64% (40/63). Twenty-six children were included for follow-up (median age 55 months). Severe neurodevelopmental impairment (NDI) was detected in 15% (4/26). Three out of 4 children with severe NDI had associated causes contributing to the impairment. Overall adverse outcome, including perinatal mortality or NDI, was 55% (27/49). Fifteen percent (4/26) had severe respiratory sequelae. Parents did not report more behavioral problems than Dutch norms. DISCUSSION: Our results suggest that severe NDI in this specific high-risk cohort occurs in 15%, which is above the range of the incidence of NDI reported in case series treated with other fetal therapies (5-10%). Large multicenter studies and an international web-based registry are warranted to prospectively gather outcome data at fixed time points.