Publications by authors named "Floris Groenendaal"

279 Publications

Mammillary body atrophy and other MRI correlates of school-age outcome following neonatal hypoxic-ischemic encephalopathy.

Sci Rep 2021 Mar 3;11(1):5017. Epub 2021 Mar 3.

Department of Neonatology, UMC Utrecht Brain Centre, Wilhelmina Children's Hospital, University Utrecht, Internal Room Number KE04.123.1, Lundlaan 6, 3508AB, Utrecht, The Netherlands.

The mammillary bodies (MB) and hippocampi are important for memory function and are often affected following neonatal hypoxic ischemic encephalopathy (HIE). The aim of this study was to assess neurodevelopmental outcome in 10-year-old children with HIE with and without therapeutic hypothermia. Additional aims were to assess the associations between MB atrophy, brain volumes (including the hippocampi), white matter microstructure and neurodevelopmental outcome at school-age. Ten-year-old children with HIE were included, who were treated with therapeutic hypothermia (n = 22) or would have qualified but were born before this became standard of care (n = 28). Children completed a neuropsychological and motor assessment and MRI. Mammillary bodies were scored as normal or atrophic at 10 years. Brain volumes were segmented on childhood MRI and DTI scans were analysed using tract-based spatial statistics. Children with HIE suffered from neurocognitive and memory problems at school-age, irrespective of hypothermia. Hippocampal volumes and MB atrophy were associated with total and performance IQ, processing speed and episodic memory in both groups. Normal MB and larger hippocampi were positively associated with global fractional anisotropy. In conclusion, injury to the MB and hippocampi was associated with neurocognition and memory at school-age in HIE and might be an early biomarker for neurocognitive and memory problems.
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http://dx.doi.org/10.1038/s41598-021-83982-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7930036PMC
March 2021

Mammillary body injury in neonatal encephalopathy: a multicentre, retrospective study.

Pediatr Res 2021 Mar 2. Epub 2021 Mar 2.

School of Psychology, College of Biomedical and Life Sciences, Cardiff University, Cardiff, UK.

Background: The mammillary bodies (MBs) have repeatedly been shown to be critical for memory, yet little is known about their involvement in numerous neurological conditions linked to memory impairments, including neonatal encephalopathy.

Methods: We implemented a multicentre retrospective study, assessing magnetic resonance scans of 219 infants with neonatal encephalopathy who had undergone hypothermia treatment in neonatal intensive care units located in the Netherlands and Italy.

Results: Abnormal MB signal was observed in ~40% of infants scanned; in half of these cases, the brain appeared otherwise normal. MB involvement was not related to the severity of encephalopathy or the pattern/severity of hypoxic-ischaemic brain injury. Follow-up scans were available for 18 cases with abnormal MB signal; in eight of these cases, the MBs appeared severely atrophic.

Conclusions: This study highlights the importance of assessing the status of the MBs in neonatal encephalopathy; this may require changes to scanning protocols to ensure that the slices are sufficiently thin to capture the MBs. Furthermore, long-term follow-up of infants with abnormal MB signal is needed to determine the effects on cognition, which may enable the use of early intervention strategies. Further research is needed to assess the role of therapeutic hypothermia in MB involvement in neonatal encephalopathy.

Impact: The MBs are particularly sensitive to hypoxia in neonates. Current hypothermia treatment provides incomplete protection against MB injury. MB involvement is likely overlooked as it can often occur when the rest of the brain appears normal. Given the importance of the MBs for memory, it is necessary that this region is properly assessed in neonatal encephalopathy. This may require improvements in scanning protocols.
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http://dx.doi.org/10.1038/s41390-021-01436-3DOI Listing
March 2021

Effect of therapeutic hypothermia on renal and myocardial function in asphyxiated (near) term neonates: A systematic review and meta-analysis.

PLoS One 2021 25;16(2):e0247403. Epub 2021 Feb 25.

Department of Neonatology, Wilhelmina Children's Hospital, University Medical Centre Utrecht and Utrecht University, Utrecht, The Netherlands.

Background: Therapeutic hypothermia (TH) is a well-established neuroprotective therapy applied in (near) term asphyxiated infants. However, little is known regarding the effects of TH on renal and/or myocardial function.

Objectives: To describe the short- and long-term effects of TH on renal and myocardial function in asphyxiated (near) term neonates.

Methods: An electronic search strategy incorporating MeSH terms and keywords was performed in October 2019 and updated in June 2020 using PubMed and Cochrane databases. Inclusion criteria consisted of a RCT or observational cohort design, intervention with TH in a setting of perinatal asphyxia and available long-term results on renal and myocardial function. We performed a meta-analysis and heterogeneity and sensitivity analyses using a random effects model. Subgroup analysis was performed on the method of cooling.

Results: Of the 107 studies identified on renal function, 9 were included. None of the studies investigated the effects of TH on long-term renal function after perinatal asphyxia. The nine included studies described the effect of TH on the incidence of acute kidney injury (AKI) after perinatal asphyxia. Meta-analysis showed a significant difference between the incidence of AKI in neonates treated with TH compared to the control group (RR = 0.81; 95% CI 0.67-0.98; p = 0.03). No studies were found investigating the long-term effects of TH on myocardial function after neonatal asphyxia. Possible short-term beneficial effects were presented in 4 out of 5 identified studies, as observed by significant reductions in cardiac biomarkers and less findings of myocardial dysfunction on ECG and cardiac ultrasound.

Conclusions: TH in asphyxiated neonates reduces the incidence of AKI, an important risk factor for chronic kidney damage, and thus is potentially renoprotective. No studies were found on the long-term effects of TH on myocardial function. Short-term outcome studies suggest a cardioprotective effect.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0247403PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7906340PMC
February 2021

Pathophysiology of Cerebral Hyperperfusion in Term Neonates With Hypoxic-Ischemic Encephalopathy: A Systematic Review for Future Research.

Front Pediatr 2021 2;9:631258. Epub 2021 Feb 2.

Department of Neonatology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands.

Worldwide neonatal hypoxic-ischemic encephalopathy (HIE) is a common cause of mortality and neurologic disability, despite the implementation of therapeutic hypothermia treatment. Advances toward new neuroprotective interventions have been limited by incomplete knowledge about secondary injurious processes such as cerebral hyperperfusion commonly observed during the first 1-5 days after asphyxia. Cerebral hyperperfusion is correlated with adverse neurodevelopmental outcome and it is a process that remains poorly understood. In order to provide an overview of the existing knowledge on the pathophysiology and highlight the gaps in current understanding of cerebral hyperperfusion in term animals and neonates with HIE, we performed a systematic research. We included papers scoping for study design, population, number of participants, study technique and relevant findings. Methodological quality was assessed using the checklist for cohort studies from The Joanna Briggs Institute. Out of 2,690 results, 34 studies were included in the final review-all prospective cohort studies. There were 14 studies of high, 17 moderate and 3 of low methodological quality. Data from the literature were analyzed in two main subjects: (1) Hemodynamic Changes subdivided into macro- and microscopic hemodynamic changes, and (2) Endogenous Pathways which was subdivided into N-methyl-D-aspartate/Mitogen activated protein kinase (NDMA/MAPK), Nitric Oxide (NO), prostanoids and other endogenous studies. Cerebral hyperperfusion in term neonates with HIE was found to be present 10-30 min after the hypoxic-ischemic event and was still present around day 10 and up to 1 month after birth. Cerebral hyperperfusion was also characterized by angiogenesis and cerebral vasodilation. Additionally, cerebral vasodilation was mediated by endogenous pathways such as MAPK through urokinase Plasminogen Activator (uPA), by neuronal NO synthase following NMDA and by prostanoid synthesis. Future research should elucidate the precise role of NMDA, MAPK and prostanoids in cerebral hyperperfusion. Moreover, research should focus on possible interventions and the effect of hypothermia on hyperperfusion. These findings should be taken into account simultaneously with brain imagining techniques, becoming a valuable asset in assessing the impact in neurodevelopmental outcome.
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http://dx.doi.org/10.3389/fped.2021.631258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884860PMC
February 2021

Evidence-based interventions to reduce mortality among preterm and low-birthweight neonates in low-income and middle-income countries: a systematic review and meta-analysis.

BMJ Glob Health 2021 Feb;6(2)

Julius Global Health, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands.

Background: Preterm birth is the leading cause of under-five-mortality worldwide, with the highest burden in low-income and middle-income countries (LMICs). The aim of this study was to synthesise evidence-based interventions for preterm and low birthweight (LBW) neonates in LMICs, their associated neonatal mortality rate (NMR), and barriers and facilitators to their implementation. This study updates all existing evidence on this topic and reviews evidence on interventions that have not been previously considered in current WHO recommendations.

Methods: Six electronic databases were searched until 3 March 2020 for randomised controlled trials reporting NMR of preterm and/or LBW newborns following any intervention in LMICs. Risk ratios for mortality outcomes were pooled where appropriate using a random effects model (PROSPERO registration number: CRD42019139267).

Results: 1236 studies were identified, of which 49 were narratively synthesised and 9 contributed to the meta-analysis. The studies included 39 interventions in 21 countries with 46 993 participants. High-quality evidence suggested significant reduction of NMR following antenatal corticosteroids (Pakistan risk ratio (RR) 0.89; 95% CI 0.80 to 0.99|Guatemala 0.74; 0.68 to 0.81), single cord (0.65; 0.50 to 0.86) and skin cleansing with chlorhexidine (0.72; 0.55 to 0.95), early BCG vaccine (0.64; 0.48 to 0.86; I 0%), community kangaroo mother care (OR 0.73; 0.55 to 0.97; I 0%) and home-based newborn care (preterm 0.25; 0.14 to 0.48|LBW 0.42; 0.27 to 0.65). No effects on perinatal (essential newborn care 1.02; 0.91 to 1.14|neonatal resuscitation 0.95; 0.84 to 1.07) or 7-day NMR (essential newborn care 1.03; 0.83 to 1.27|neonatal resuscitation 0.92; 0.77 to 1.09) were observed after training birth attendants.

Conclusion: The findings of this study encourage the implementation of additional, evidence-based interventions in the current (WHO) guidelines and to be selective in usage of antenatal corticosteroids, to reduce mortality among preterm and LBW neonates in LMICs. Given the global commitment to end all preventable neonatal deaths by 2030, continuous evaluation and improvement of the current guidelines should be a priority on the agenda.
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http://dx.doi.org/10.1136/bmjgh-2020-003618DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7896575PMC
February 2021

Timing of Intervention for Post-Hemorrhagic Ventricular Dilatation: An Ongoing Debate.

J Pediatr 2021 Feb 13. Epub 2021 Feb 13.

Department of Neonatology, Wilhelmina Children's Hospital, University Medical Center, Utrecht and Utrecht University, Utrecht, The Netherlands; University Medical Center Utrecht, Utrecht Brain Center, The Netherlands. Electronic address:

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http://dx.doi.org/10.1016/j.jpeds.2021.02.022DOI Listing
February 2021

Isoprostanes as Biomarker for White Matter Injury in Extremely Preterm Infants.

Front Pediatr 2020 15;8:618622. Epub 2021 Jan 15.

Department of Neonatology, University Medical Center Utrecht and Utrecht University, Utrecht, Netherlands.

Preterm white matter is vulnerable to lipid peroxidation-mediated injury. F2-isoprostanes (IPs), are a useful biomarker for lipid peroxidation. Aim was to assess the association between early peri-postnatal IPs, white matter injury (WMI) at term equivalent age (TEA), and neurodevelopmental outcome in preterm infants. Infants with a gestational age (GA) below 28 weeks who had an MRI at TEA were included. IPs were measured in cord blood (cb) at birth and on plasma (pl) between 24 and 48 h after birth. WMI was assessed using Woodward MRI scoring system. Multiple regression analyses were performed to assess the association between IPs with WMI and then with BSITD-III scores at 24 months corrected age (CA). Receiver operating characteristic (ROC) curve analysis was used to evaluate the predictive value of pl-IPs for the development of WMI. Forty-four patients were included. cb-IPs were not correlated with WMI score at TEA, whereas higher pl-IPs and lower GA predicted higher WMI score ( = 0.037 and 0.006, respectively) after controlling for GA, FiO2 at sampling and severity of IVH. The area under the curve was 0.72 (CI 95% = 0.51-0.92). The pl-IPs levels plotted curve indicated that 31.8 pg/ml had the best predictive threshold with a sensitivity of 86% and a specificity of 60%, to discriminate newborns with any WMI from newborns without WMI. IPs were not associated with outcome at 24 months. Early measurement of pl-IPs may help discriminate patients showing abnormal WMI score at TEA, thus representing an early biomarker to identify newborns at risk for brain injury.
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http://dx.doi.org/10.3389/fped.2020.618622DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7874160PMC
January 2021

Background incidence rates of adverse pregnancy outcomes in the Netherlands: Data of 2006-2018.

Eur J Obstet Gynecol Reprod Biol 2021 Jan 25;256:274-280. Epub 2020 Nov 25.

Centre for Infectious Disease Control, National Institute for Public Health and the Environment, Bilthoven, the Netherlands.

Objective: Maternal vaccination is an effective and safe intervention to protect newborns against infectious diseases shortly after birth. We assessed background rates of adverse pregnancy outcomes before the implementation of a maternal pertussis immunisation programme in the Netherlands, to put into perspective the safety concerns about such outcomes following immunisation.

Study Design: In this retrospective cross-sectional study, annual numbers of pregnancy outcomes derived from the Dutch Perinatal Registry were used to calculate incidence rates per 10,000 in the 2006-2018 period. Births of ≥500 g birth weight and ≥24 + 0 w gestational age were included. Trends with moving-average-lines over the past 3 years were plotted, with 95 % confidence interval.

Results: From 2006 through 2018, yearly numbers of pregnancies ranged between 158,868-175,710. Numbers of newborns ranged between 161,307-178,874, of whom 160,838-178,177 were live-born. Most outcomes were stable over time. Between 2006-2011, occurrence of labour induction increased by 68 %, and postpartum hemorrhage increased by 25 %. Both stabilised from 2011 onwards. Perinatal mortality up to day 7 or 28 postpartum decreased by 38 % and 37 %, respectively. Occurrence of low Apgar score among preterm infants born before 37 + 0 w gestational age and among term infants increased by 19 % and 27 %, respectively.

Conclusion: Our study on background incidences showed notable increases over time in occurrence of labour induction, postpartum hemorrhage and low Apgar score, while showing a considerable decrease in overall perinatal mortality. These findings should be considered when interpreting data on adverse events occurring since the maternal pertussis immunisation programme was implemented.
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http://dx.doi.org/10.1016/j.ejogrb.2020.11.064DOI Listing
January 2021

Survival and causes of death in extremely preterm infants in the Netherlands.

Arch Dis Child Fetal Neonatal Ed 2020 11 6. Epub 2020 Nov 6.

Department of Neonatology, Máxima Medical Centre, Veldhoven, The Netherlands.

Objective: In the Netherlands, the threshold for offering active treatment for spontaneous birth was lowered from 25 to 24 weeks' gestation in 2010. This study aimed to evaluate the impact of guideline implementation on survival and causes and timing of death in the years following implementation.

Design: National cohort study, using data from the Netherlands Perinatal Registry.

Patients: The study population included all 3312 stillborn and live born infants with a gestational age (GA) between 24 and 26 weeks born between January 2011 and December 2017. Infants with the same GA born between January 2007 and December 2009 (N=1400) were used as the reference group.

Main Outcome Measures: Survival to discharge, as well as cause and timing of death.

Results: After guideline implementation, there was a significant increase in neonatal intensive care unit (NICU) admission rate for live born infants born at 24 weeks' GA (27%-69%, p<0.001), resulting in increased survival to discharge in 24-week live born infants (13%-34%, p<0.001). Top three causes of in-hospital mortality were necrotising enterocolitis (28%), respiratory distress syndrome (19%) and intraventricular haemorrhage (17%). A significant decrease in cause of death either complicated or caused by respiratory insufficiency was seen over time (34% in 2011-2014 to 23% in 2015-2017, p=0.006).

Conclusions: Implementation of the 2010 guideline resulted as expected in increased NICU admissions rate and postnatal survival of infants born at 24 weeks' GA. In the years after implementation, a shift in cause of death was seen from respiratory insufficiency towards necrotising enterocolitis and sepsis.
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http://dx.doi.org/10.1136/archdischild-2020-318978DOI Listing
November 2020

Association of early skin breaks and neonatal thalamic maturation: A modifiable risk?

Neurology 2020 12 21;95(24):e3420-e3427. Epub 2020 Oct 21.

From the Department of Paediatrics (E.G.D., V.C., T.G., S.P.M.), the Hospital for Sick Children and the University of Toronto; Faculty of Education (E.G.D.), Western University, London; Department of Pediatrics (R.E.G., A.S.), University of British Columbia, Vancouver, Canada; Department of Neonatology (F.G., M.B., N.W., C.K., L.d.V.), Utrecht Brain Center (F.G., M.B., L.d.V.), and Child Development and Exercise Center (R.E.), University Medical Center Utrecht, Utrecht University, the Netherlands; Cerebral Imaging Centre (M.M.C.), Douglas Institute, Verdun; and Departments of Psychiatry (M.M.C.) and Biological and Biomedical Engineering (M.M.C.), McGill University, Montreal, Canada.

Objective: To test the hypothesis that a strategy of prolonged arterial line (AL) and central venous line (CVL) use is associated with reduced neonatal invasive procedures and improved growth of the thalamus in extremely preterm neonates (<28 weeks' gestation).

Methods: Two international cohorts of very preterm neonates (n = 143) with prolonged (≥14 days) or restricted (<14 days) use of AL/CVL were scanned serially with MRI. General linear models were used to determine the association between skin breaks and thalamic volumes, accounting for clinical confounders and site differences. Children were assessed at preschool age on standardized tests of motor and cognitive function. Outcome scores were assessed in relation to neonatal thalamic growth.

Results: Prolonged AL/CVL use in neonates (n = 86) was associated with fewer skin breaks (median 34) during the hospital stay compared to restricted AL/CVL use (n = 57, median 91, 95% confidence interval [CI] 60.35-84.89). Neonates with prolonged AL/CVL use with fewer skin breaks had significantly larger thalamic volumes early in life compared to neonates with restricted line use (B = 121.8, = 0.001, 95% CI 48.48-195.11). Neonatal thalamic growth predicted preschool-age cognitive (B = 0.001, 95% CI 0.0003-0.001, = 0.002) and motor scores (B = 0.01, 95% CI 0.001-0.10, = 0.02). Prolonged AL/CVL use was not associated with greater incidence of sepsis or multiple infections.

Conclusions: Prolonged AL/CVL use in preterm neonates may provide an unprecedented opportunity to reduce invasive procedures in preterm neonates. Pain reduction in very preterm neonates is associated with optimal thalamic growth and neurodevelopment.
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http://dx.doi.org/10.1212/WNL.0000000000010953DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7836658PMC
December 2020

Cerebellar injury in term neonates with hypoxic-ischemic encephalopathy is underestimated.

Pediatr Res 2020 Sep 23. Epub 2020 Sep 23.

Department of Neonatology, Wilhelmina Children's Hospital, University Medical Center Utrecht Brain Center, University Utrecht, Utrecht, The Netherlands.

Background: Postmortem examinations frequently show cerebellar injury in infants with severe hypoxic-ischemic encephalopathy (HIE), while it is less well visible on MRI. The primary aim was to investigate the correlation between cerebellar apparent diffusion coefficient (ADC) values and histopathology in infants with HIE. The secondary aim was to compare ADC values in the cerebellum of infants with HIE and infants without brain injury.

Methods: ADC values in the cerebellar vermis, hemispheres and dentate nucleus (DN) of (near-)term infants with HIE (n = 33) within the first week after birth were compared with neonates with congenital non-cardiac anomalies, normal postoperative MRIs and normal outcome (n = 22). Microglia/macrophage activation was assessed using CD68 and/or HLA-DR staining and Purkinje cell (PC) injury using H&E-stained slices. The correlation between ADC values and the histopathological measures was analyzed.

Results: ADC values in the vermis (p = 0.021) and DN (p < 0.001) were significantly lower in infants with HIE compared to controls. ADC values in the cerebellar hemispheres were comparable. ADC values in the vermis were correlated with the number and percentage of normal PCs; otherwise ADC values and histology were not correlated.

Conclusion: Histopathological injury in the cerebellum is common in infants with HIE. ADC values underestimate histopathological injury.

Impact: ADC values might underestimate cerebellar injury in neonates with HIE. ADC values in the vermis and dentate nucleus of infants with HIE are lower compared to controls, but not in the cerebellar hemispheres. Abnormal ADC values are only found when cytotoxic edema is very severe. ADC values in the vermis are correlated with Purkinje cell injury in the vermis; furthermore, there were no correlations between ADC values and histopathological measures.
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http://dx.doi.org/10.1038/s41390-020-01173-zDOI Listing
September 2020

Increased Use of Therapeutic Hypothermia in Infants with Milder Neonatal Encephalopathy due to Presumed Perinatal Asphyxia.

Neonatology 2020 19;117(4):488-494. Epub 2020 Aug 19.

Department of Neonatology, Wilhelmina Children's Hospital, University Medical Center Utrecht and Utrecht University, Utrecht, The Netherlands,

Introduction: Adverse outcomes have been reported in infants with mild neonatal encephalopathy (NE). Increasing clinical experience with the application of therapeutic hypothermia (TH) may have resulted in the treatment of newborns with milder NE during recent years.

Objective: To determine whether infants treated with TH in the initial years following implementation had a higher degree of NE than infants treated during subsequent years.

Methods: Infants with NE treated with TH from February 2008 until July 2017 were included. Thompson and Sarnat scores, amplitude-integrated electroencephalography (aEEG) background patterns before the start of TH, and neurodevelopmental outcome at 2 years were compared between infants treated from February 2008 until October 2012 (period 1) and infants treated from November 2012 until July 2017 (period 2).

Results: 211 newborns with NE were treated with TH (period 1: n = 109, period 2: n = 102). Sarnat scores in period 1 and 2 were mild in 7.3 vs. 28.4%, moderate in 66.1 vs. 44.1%, and severe in 26.6 vs. 22.5%, respectively (p = 0.008). Thompson scores were lower in period 2 (median = 9, IQR 7-12) than in period 1 (median = 10, IQR 8.5-13.5, p = 0.018). The aEEGs and neurodevelopmental outcomes were comparable between the periods.

Conclusions: Based on Thompson and Sarnat scores, but not aEEG background patterns, infants treated during the second period had milder NE than infants treated during the first years following implementation of TH. There was no difference in 2 years neurodevelopmental outcome. Further research is necessary to evaluate the value of TH for infants with clinically mild NE.
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http://dx.doi.org/10.1159/000508710DOI Listing
August 2020

Delay in Treatment of Neonatal Seizures: A Retrospective Cohort Study.

Neonatology 2020 19;117(5):599-605. Epub 2020 Aug 19.

Department of Neonatology, Wilhelmina Children's Hospital, University Medical Centre Utrecht, Utrecht, The Netherlands,

Introduction: Neonatal seizures are common and caused by a variety of underlying disorders. There is increasing evidence that neonatal seizures result in further brain damage.

Objective: To describe the time interval between diagnosis of amplitude-integrated electroencephalography (aEEG)-confirmed seizures and administration of anti-epileptic drugs (AEDs).

Methods: Single-centre retrospective cohort study, with full-term infants (n = 106) admitted to a level III neonatal intensive care unit between 2012 and 2017 with seizures confirmed on 2-channel aEEG and corresponding raw electroencephalography traces, treated with AEDs. The time interval between the first seizure on the aEEG registration and AED administration was calculated. Factors associated with early treatment were analysed.

Results: The median time interval of initiating treatment of aEEG-confirmed seizures was 01:50 h (interquartile range 00:43-4:30 h). Treatment of aEEG-confirmed seizures was initiated <1 h in 34/106 infants (32.1%), between 1 and 2 h in 21/106 infants (19.8%), 2-4 h in 23/106 infants (21.7%), 4-8 h in 14/106 infants (13.2%), and ≥8 h in 14/106 infants (13.2%). Seizures treated <1 h were significantly more often recognized by the seizure detection algorithm (SDA) compared to seizures treated >1 h (67 vs. 42%, p = 0.02) and showed more clinical signs (79.4 vs. 37.5%, p < 0.01). There was no difference for out-of-office hours (23.5 vs. 22.2%, p = 0.88).

Conclusion: With only 32.1% of the seizures being treated <1 h, there is room for improvement. Timely treatment occurred more often when seizures were clinical or recognised by the SDA. aEEG is a helpful tool for diagnosing seizures 24/7.
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http://dx.doi.org/10.1159/000509282DOI Listing
August 2020

Randomized Controlled Early versus Late Ventricular Intervention Study in Posthemorrhagic Ventricular Dilatation: Outcome at 2 Years.

J Pediatr 2020 08 12. Epub 2020 Aug 12.

Department of Neonatology, Wilhelmina Children's Hospital, University Medical Center; Utrecht; University Medical Center Utrecht, Utrecht Brain Center, Utrecht, the Netherlands. Electronic address:

Objective: To compare the effect of intervention at low vs high threshold of ventriculomegaly in preterm infants with posthemorrhagic ventricular dilatation on death or severe neurodevelopmental disability.

Study Design: This multicenter randomized controlled trial reviewed lumbar punctures initiated after either a low threshold (ventricular index of >p97 and anterior horn width of >6 mm) or high threshold (ventricular index of >p97 + 4 mm and anterior horn width of >10 mm). The composite adverse outcome was defined as death or cerebral palsy or Bayley composite cognitive/motor scores <-2 SDs at 24 months corrected age.

Results: Outcomes were assessed in 113 of 126 infants. The composite adverse outcome was seen in 20 of 58 infants (35%) in the low threshold group and 28 of 55 (51%) in the high threshold (P = .07). The low threshold intervention was associated with a decreased risk of an adverse outcome after correcting for gestational age, severity of intraventricular hemorrhage, and cerebellar hemorrhage (aOR, 0.24; 95% CI, 0.07-0.87; P = .03). Infants with a favorable outcome had a smaller fronto-occipital horn ratio (crude mean difference, -0.06; 95% CI, -0.09 to -0.03; P < .001) at term-equivalent age. Infants in the low threshold group with a ventriculoperitoneal shunt, had cognitive and motor scores similar to those without (P = .3 for both), whereas in the high threshold group those with a ventriculoperitoneal shunt had significantly lower scores than those without a ventriculoperitoneal shunt (P = .01 and P = .004, respectively).

Conclusions: In a post hoc analysis, earlier intervention was associated with a lower odds of death or severe neurodevelopmental disability in preterm infants with progressive posthemorrhagic ventricular dilatation.

Trial Registration: ISRCTN43171322.
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http://dx.doi.org/10.1016/j.jpeds.2020.08.014DOI Listing
August 2020

Increase in treatment of retinopathy of prematurity in the Netherlands from 2010 to 2017.

Acta Ophthalmol 2021 Feb 23;99(1):97-103. Epub 2020 Jul 23.

Leiden University Medical Center, Leiden, Netherlands.

Purpose: Compare patients treated for Retinopathy of Prematurity (ROP) in two consecutive periods.

Methods: Retrospective inventory of anonymized neonatal and ophthalmological data of all patients treated for ROP from 2010 to 2017 in the Netherlands, subdivided in period (P)1: 1-1-2010 to 31-3-2013 and P2: 1-4-2013 to 31-12-2016. Treatment characteristics, adherence to early treatment for ROP (ETROP) criteria, outcome of treatment and changes in neonatal parameters and policy of care were compared.

Results: Overall 196 infants were included, 57 infants (113 eyes) in P1 and 139 (275 eyes) in P2, indicating a 2.1-fold increase in ROP treatment. No differences were found in mean gestational age (GA) (25.9 ± 1.7 versus 26.0 ± 1.7 weeks, p = 0.711), mean birth weight (791 ± 311 versus 764 ± 204 grams, p = 0.967) and other neonatal risk factors for ROP. In P2, the number of premature infants born <25 weeks increased by factor 1.23 and higher oxygen saturation levels were aimed at in most centres. At treatment decision, 59.6% (P1) versus 83.5% (P2) (p = 0.263) infants were classified as Type 1 ROP (ETROP classification). Infants were treated with laser photocoagulation (98 versus 96%) and intravitreal bevacizumab (2 versus 4%). Retreatment was necessary in 10 versus 21 (p = 0.160). Retinal detachment developed in 6 versus 13 infants (p = 0.791) of which 2 versus 6 bilateral (p = 0.599).

Conclusion: In period 2, the number of infants treated according to the ETROP criteria (Type 1) increased, the number of ROP treatments, retinal detachments and retreatments doubled and the absolute number of retinal detachments increased. Neonatal data did not provide a decisive explanation, although changes in neonatal policy were reported.
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http://dx.doi.org/10.1111/aos.14501DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7891652PMC
February 2021

Non-right-handedness in children born extremely preterm: Relation to early neuroimaging and long-term neurodevelopment.

PLoS One 2020 6;15(7):e0235311. Epub 2020 Jul 6.

Department of Neonatology, Wilhelmina Children's Hospital, University Medical Centre Utrecht, Utrecht University, Utrecht, The Netherlands.

Objective: This study aimed to define the prevalence and predictors of non-right-handedness and its link to long-term neurodevelopmental outcome and early neuroimaging in a cohort of children born extremely preterm (<28 weeks gestation).

Methods: 179 children born extremely preterm admitted to the Neonatal Intensive Care Unit of our tertiary centre from 2006-2013 were included in a prospective longitudinal cohort study. Collected data included perinatal data, demographic characteristics, neurodevelopmental outcome measured by the Bayley Scales of Infant and Toddler Development at 2 years and the Movement Assessment Battery for Children at 5 years, and handedness measured at school age (4-8 years). Magnetic resonance imaging performed at term-equivalent age was used to study overt brain injury. Diffusion tensor imaging scans were analysed using tract-based spatial statistics to assess white matter microstructure in relation to handedness and neurodevelopmental outcome.

Results: The prevalence of non-right-handedness in our cohort was 22.9%, compared to 12% in the general population. Weaker fine motor skills at 2 years and paternal non-right-handedness were significantly associated with non-right-handedness. Both overt brain injury and fractional anisotropy of white matter structures on diffusion tensor images were not related to handedness. Fractional anisotropy measurements showed significant associations with neurodevelopmental outcome.

Conclusions: Our data show that non-right-handedness in children born extremely preterm occurs almost twice as frequently as in the general population. In the studied population, non-right-handedness is associated with weaker fine motor skills and paternal non-right-handedness, but not with overt brain injury or microstructural brain development on early magnetic resonance imaging.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0235311PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7337339PMC
September 2020

Prediction of Drug Exposure in Critically Ill Encephalopathic Neonates Treated With Therapeutic Hypothermia Based on a Pooled Population Pharmacokinetic Analysis of Seven Drugs and Five Metabolites.

Clin Pharmacol Ther 2020 Nov 27;108(5):1098-1106. Epub 2020 Jun 27.

Department of Clinical Pharmacy, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.

Drug dosing in encephalopathic neonates treated with therapeutic hypothermia is challenging; exposure is dependent on body size and maturation but can also be influenced by factors related to disease and treatment. A better understanding of underlying pharmacokinetic principles is essential to guide drug dosing in this population. The prospective multicenter cohort study PharmaCool was designed to investigate the pharmacokinetics of commonly used drugs in neonatal encephalopathy. In the present study, all data obtained in the PharmaCool study were combined to study the structural system specific effects of body size, maturation, recovery of organ function, and temperature on drug clearance using nonlinear mixed effects modeling. Data collected during the first 5 days of life from 192 neonates treated with therapeutic hypothermia were included. An integrated population pharmacokinetic model of seven drugs (morphine, midazolam, lidocaine, phenobarbital, amoxicillin, gentamicin, and benzylpenicillin) and five metabolites (morphine-3-glucuronide, morphine-6-glucuronide, 1-hydroxymidazolam, hydroxymidazolam glucuronide, and monoethylglycylxylidide) was successfully developed based on previously developed models for the individual drugs. For all compounds, body size was related to clearance using allometric relationships and maturation was described with gestational age in a fixed sigmoidal Hill equation. Organ recovery after birth was incorporated using postnatal age. Clearance increased by 1.23%/hours of life (95% confidence interval (CI) 1.03-1.43) and by 0.54%/hours of life (95% CI 0.371-0.750) for high and intermediate clearance compounds, respectively. Therapeutic hypothermia reduced clearance of intermediate clearance compounds only, by 6.83%/°C (95% CI 5.16%/°C-8.34%/°C). This integrated model can be used to facilitate drug dosing and future pharmacokinetic studies in this population.
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http://dx.doi.org/10.1002/cpt.1917DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7689752PMC
November 2020

Increase in Brain Volumes after Implementation of a Nutrition Regimen in Infants Born Extremely Preterm.

J Pediatr 2020 08 7;223:57-63.e5. Epub 2020 May 7.

Department of Neonatology, Wilhelmina Children's Hospital, Utrecht, the Netherlands; Brain Centre Rudolf Magnus, University Medical Centre Utrecht, Utrecht, the Netherlands. Electronic address:

Objective: To assess the effect of early life nutrition on structural brain development in 2 cohorts of extremely preterm infants, before and after the implementation of a nutrition regimen containing more protein and lipid.

Study Design: We included 178 infants retrospectively (median gestational age, 26.6 weeks; IQR, 25.9-27.3), of whom 99 received the old nutrition regimen (cohort A, 2011-2013) and 79 the new nutrition regimen (cohort B, 2013-2015). Intake of protein, lipids, and calories was calculated for the first 28 postnatal days. Brain magnetic resonance imaging (MRI) was performed at 30 weeks postmenstrual age (IQR, 30.3-31.4) and term-equivalent age (IQR, 40.9-41.4). Volumes of 42 (left + right) brain structures were calculated.

Results: Mean protein and caloric intake in cohort B (3.4 g/kg per day [P < .001] and 109 kcal/kg per day [P = .038]) was higher than in cohort A (2.7 g/kg per day; 104 kcal/kg per day). At 30 weeks, 22 regions were significantly larger in cohort B compared with cohort A, whereas at term-equivalent age, only the caudate nucleus was significantly larger in cohort B compared with cohort A.

Conclusions: An optimized nutrition protocol in the first 28 days of life is associated with temporarily improved early life brain volumes.
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http://dx.doi.org/10.1016/j.jpeds.2020.04.063DOI Listing
August 2020

Predictors of Outcomes in Hypoxic-Ischemic Encephalopathy following Hypothermia: A Meta-Analysis.

Neonatology 2020 1;117(4):411-427. Epub 2020 Apr 1.

Department of Neonatology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, The Netherlands.

Introduction: Prediction of neurodevelopmental outcome in infants with hypoxic-ischemic encephalopathy remains an important challenge. Various studies have shown that the predictive ability of different modalities changed after the introduction of therapeutic hypothermia. This paper reviews the diagnostic test accuracy of the different modalities that are being used to predict neurodevelopmental outcomes following therapeutic hypothermia.

Methods: A systematic literature search was performed using Embase and PubMed. Two reviewers independently included eligible studies and extracted data. The quality of the studies was assessed using the Quality in Prognosis Studies Tool. Meta-analyses were performed where possible.

Results: Forty-seven articles and 3 conference abstracts were included, reporting on 3,072infants of whom 39% died or had an adverse neurodevelopmental outcome. A meta-analysis could be performed using 37 articles on (amplitude-integrated) electroencephalography (EEG), conventional magnetic resonance imaging (MRI), diffusion-weighted imaging (DWI), and proton magnetic resonance spectroscopy (1H-MRS). Amplitude-integrated EEG (aEEG) at 24 and 72 h showed similar high diagnostic OR, while aEEG at 6 h and EEG performed less, both due to a low specificity. For MRI, most studies reported scoring systems in which early (<8 days) MRI performed better than late (≥8 days) MRI. Injury to the posterior limb of the internal capsule on MRI or to the thalami on DWI were strong individual predictors, as was an increased lactate/N-acetylaspartate peak on 1H-MRS.

Conclusions: In the era of therapeutic hypothermia, the different modalities remain good predictors of neurodevelopmental outcome. However, timing should be taken into account. aEEG may initially be false positive and gets more reliable after 24 h. In contrast, MRI should be used during the first week, as its predictive value decreases afterwards.
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http://dx.doi.org/10.1159/000505519DOI Listing
April 2020

The development and validation of a cerebral ultrasound scoring system for infants with hypoxic-ischaemic encephalopathy.

Pediatr Res 2020 03;87(Suppl 1):59-66

Department of Neonatology, Wilhelmina Children's Hospital, University Medical Centre Utrecht, Utrecht University, Utrecht, the Netherlands.

Background: Hypoxic-ischaemic encephalopathy (HIE) is an important cause of morbidity and mortality in neonates. When the gold standard MRI is not feasible, cerebral ultrasound (CUS) might offer an alternative. In this study, the association between a novel CUS scoring system and neurodevelopmental outcome in neonates with HIE was assessed.

Methods: (Near-)term infants with HIE and therapeutic hypothermia, a CUS on day 1 and day 3-7 after birth and available outcome data were retrospectively included in cohort I. CUS findings on day 1 and day 3-7 were related to adverse outcome in univariate and the CUS of day 3-7 also in multivariable logistic regression analyses. The resistance index, the sum of deep grey matter and of white matter involvement were included in multivariable logistic regression analyses. A comparable cohort from another hospital was used for validation (cohort II).

Results: Eighty-three infants were included in cohort I and 35 in cohort II. The final CUS scoring system contained the sum of white matter (OR = 2.6, 95% CI 1.5-4.7) and deep grey matter involvement (OR = 2.7, 95% CI 1.7-4.4). The CUS scoring system performed well in cohort I (AUC = 0.90) and II (AUC = 0.89).

Conclusion: This validated CUS scoring system is associated with neurodevelopmental outcome in neonates with HIE.
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http://dx.doi.org/10.1038/s41390-020-0782-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7098882PMC
March 2020

Preterm infants with isolated cerebellar hemorrhage show bilateral cortical alterations at term equivalent age.

Sci Rep 2020 03 24;10(1):5283. Epub 2020 Mar 24.

Department of Neonatology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.

The cerebellum is connected to numerous regions of the contralateral side of the cerebrum. Motor and cognitive deficits following neonatal cerebellar hemorrhages (CbH) in extremely preterm neonates may be related to remote cortical alterations, following disrupted cerebello-cerebral connectivity as was previously shown within six CbH infants. In this retrospective case series study, we used MRI and advanced surface-based analyses to reconstruct gray matter (GM) changes in cortical thickness and cortical surface area in extremely preterm neonates (median age = 26; range: 24.9-26.7 gestational weeks) with large isolated unilateral CbH (N = 5 patients). Each CbH infant was matched with their own preterm infant cohort (range: 20-36 infants) based on sex and gestational age at birth. On a macro level, our data revealed that the contralateral cerebral hemisphere of CbH neonates did not show less cortical thickness or cortical surface area than their ipsilateral cerebral hemisphere at term. None of the cases differed from their matched cohort groups in average cortical thickness or average cortical surface area in the ipsilateral or contralateral cerebral hemisphere. On a micro (i.e. vertex) level, we established high variability in significant local cortical GM alteration patterns across case-cohort groups, in which the cases showed thicker or bigger volume in some regions, among which the caudal middle frontal gyrus, insula and parahippocampal gyrus, and thinner or less volume in other regions, among which the cuneus, precuneus and supratentorial gyrus. This study highlights that cerebellar injury during postnatal stages may have  widespread bilateral influence on the early maturation of cerebral cortical regions, which implicate complex cerebello-cerebral interactions to be present at term birth.
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http://dx.doi.org/10.1038/s41598-020-62078-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7093404PMC
March 2020

Translation from animal to clinical studies, choosing the optimal moment.

Pediatr Res 2020 12 19;88(6):836-837. Epub 2020 Feb 19.

Department of Neonatology, Wilhelmina Children's Hospital, University Medical Center Utrecht and Utrecht University, Utrecht, the Netherlands.

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http://dx.doi.org/10.1038/s41390-020-0820-yDOI Listing
December 2020

Brain temperature of infants with neonatal encephalopathy following perinatal asphyxia calculated using magnetic resonance spectroscopy.

Pediatr Res 2020 08 2;88(2):279-284. Epub 2020 Jan 2.

Department of Radiology, University Medical Center Utrecht, University Utrecht, Utrecht, The Netherlands.

Background: Little is known about brain temperature of neonates during MRI. Brain temperature can be estimated non-invasively with proton Magnetic Resonance Spectroscopy (H-MRS), but the most accurate H-MRS method has not yet been determined. The primary aim was to estimate brain temperature using H-MRS in infants with neonatal encephalopathy (NE) following perinatal asphyxia. The secondary aim was to compare brain temperature during MRI with rectal temperatures before and after MRI.

Methods: In this retrospective study, brain temperature in 36 (near-)term infants with NE was estimated using short (36 ms) and long (288 ms) echo time (TE) H-MRS. Brain temperature was calculated using two different formulas: formula of Wu et al. and a formula based on phantom calibration. The methods were compared. Rectal temperatures were collected <3 hours before and after MRI.

Results: Brain temperatures calculated with the formula of Wu et al. and the calibrated formula were similar as well as brain temperatures derived from short and long TE H-MRS. Rectal temperature did not differ before and after MRI.

Conclusions: Brain temperature can be measured using H-MRS in daily clinical practice using the formula of Wu et al. with both short and long TE H-MRS. Brain temperature remained within physiological range during MRI.
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http://dx.doi.org/10.1038/s41390-019-0739-3DOI Listing
August 2020

Neonatal care bundles are associated with a reduction in the incidence of intraventricular haemorrhage in preterm infants: a multicentre cohort study.

Arch Dis Child Fetal Neonatal Ed 2020 Jul 15;105(4):419-424. Epub 2019 Nov 15.

Department of Neonatology, Isala Hospitals, Zwolle, The Netherlands.

Objective: To investigate the effect of a nursing intervention bundle, applied during the first 72 hours of life, on the incidence of germinal matrix-intraventricular haemorrhage (GMH-IVH) in very preterm infants.

Design: Multicentre cohort study.

Setting: Two Dutch tertiary neonatal intensive care units.

Patients: The intervention group consisted of 281 neonates, whereas 280 infants served as historical controls (gestational age for both groups <30 weeks).

Interventions: After a training period, the nursing intervention bundle was implemented and applied during the first 72 hours after birth. The bundle consisted of maintaining the head in the midline, tilting the head of the incubator and avoidance of flushing/rapid withdrawal of blood and sudden elevation of the legs.

Main Outcome Measures: The incidence of GMH-IVH occurring and/or increasing after the first ultrasound (but within 72 hours), cystic periventricular leukomalacia and/or in-hospital death was the primary composite outcome measure. Logistic regression analysis was used to explore differences between groups.

Results: The nursing intervention bundle was associated with a lower risk of developing a GMH-IVH (any degree), cystic periventricular leukomalacia and/or mortality (adjusted OR 0.42, 95% CI 0.27 to 0.65). In the group receiving the bundle, also severe GMH-IVH, cystic periventricular leukomalacia and/or death were less often observed (adjusted OR 0.54, 95% CI 0.33 to 0.91).

Conclusions: The application of a bundle of nursing interventions is associated with reduced risk of developing a new/progressive (severe) GMH-IVH, cystic periventricular leukomalacia and/or mortality in very preterm infants when applied during the first 72 hours postnatally.
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http://dx.doi.org/10.1136/archdischild-2018-316692DOI Listing
July 2020

Early prediction of unilateral cerebral palsy in infants at risk: MRI versus the hand assessment for infants.

Pediatr Res 2020 04 13;87(5):932-939. Epub 2019 Nov 13.

Department of Neonatology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.

Background: Neonates with unilateral perinatal brain injury (UPBI) are at risk for developing unilateral spastic cerebral palsy (USCP). This study compares several predictors for USCP later in life.

Methods: Twenty-one preterm and 24 term born infants with UPBI were included, with an MRI scan including diffusion tensor imaging (DTI) performed at term equivalent age or around 3 months after birth, respectively. T2-weighted images and DTI-based tractography were used to measure the surface area, diameter, and fractional anisotropy (FA) of both corticospinal tracts (CSTs). The hand assessment for infants (HAI) was performed before 5, between 5 and 8 and between 8 and 12 months of (corrected) age. Asymmetry indices were derived from all techniques and related to USCP at ≥2 years of age.

Results: MRI measures and HAI scores were significantly lower for the affected compared to the unaffected side. Before 5 months of age, FA asymmetry on DTI yielded the highest area under the curve compared to conventional MRI and HAI.

Conclusions: Prediction of USCP after UPBI is reliable using asymmetry of the CST on MRI, as well as clinical hand assessment. Before 5 months of age, DTI tractography provides strongest predictive information, while HAI specifically aids to prognosis of USCP at later age points.
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http://dx.doi.org/10.1038/s41390-019-0664-5DOI Listing
April 2020

Periventricular Hemorrhagic Infarction in Very Preterm Infants: Characteristic Sonographic Findings and Association with Neurodevelopmental Outcome at Age 2 Years.

J Pediatr 2020 02 6;217:79-85.e1. Epub 2019 Nov 6.

Department of Neonatology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, the Netherlands; Division of Neonatology, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Canada; Section of Neonatology, Department of Pediatrics, University of Calgary, Calgary, Alberta, Canada. Electronic address:

Objective: To describe the sonographic characteristics of periventricular hemorrhagic infarction (PVHI) and their association with mortality and neurodevelopmental disability in very preterm infants born in 2008-2013.

Study Design: Retrospective multicenter observational cohort study. Diagonal PVHI size was measured and severity score assessed. PVHI characteristics were scored and temporal trends were assessed. Neurodevelopmental outcome at 2 years of corrected age was assessed using either the Bayley Scales of Infant and Toddler Development, Third Edition or the Griffiths Mental Development Scales. Multigroup analyses were applied as appropriate.

Results: We enrolled 160 infants with median gestational age of 26.6 weeks. PVHI was mostly unilateral (90%), associated with an ipsilateral grade III intraventricular hemorrhage (84%), and located in the parietal lobe (51%). Sixty-four (40%) infants with PVHI died in the neonatal period. Of the survivors assessed at 2 years of corrected age, 65% had normal cognitive and 69% had normal motor outcomes. The cerebral palsy rate was 42%. The composite outcome of death or severe neurodevelopmental disability was observed in 58%, with no trends over the study period (P = .6). Increasing PVHI severity score was associated with death (P < .001). Increasing PVHI size and severity score were negatively associated with gross motor scores (P = .01 and .03, respectively). Trigone involvement was associated with cerebral palsy (41% vs 14%; P = .004). Associated posthemorrhagic ventricular dilation (36%) was an independent risk factor for poorer cognitive and motor outcomes (P < .001 for both).

Conclusions: Increasing PVHI size and severity score were predictive of less optimal gross motor outcome and death in very preterm infants.
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http://dx.doi.org/10.1016/j.jpeds.2019.09.081DOI Listing
February 2020

Two-dimensional ultrasound measurements vs. magnetic resonance imaging-derived ventricular volume of preterm infants with germinal matrix intraventricular haemorrhage.

Pediatr Radiol 2020 02 6;50(2):234-241. Epub 2019 Nov 6.

Department of Neonatology, Wilhelmina Children's Hospital/University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.

Background: Post-haemorrhagic ventricular dilatation can be measured accurately by MRI. However, two-dimensional (2-D) cranial US can be used at the bedside on a daily basis.

Objective: To assess whether the ventricular volume can be determined accurately using US.

Materials And Methods: We included 31 preterm infants with germinal matrix intraventricular haemorrhage. Two-dimensional cranial US images were acquired and the ventricular index, anterior horn width and thalamo-occipital distance were measured. In addition, cranial MRI was performed. The ventricular volume on MRI was determined using a previously validated automatic segmentation algorithm. We obtained the correlation and created a linear model between MRI-derived ventricular volume and 2-D cranial US measurements.

Results: The ventricular index, anterior horn width and thalamo-occipital distance as measured on 2-D cranial US were significantly associated with the volume of the ventricles as determined with MRI. A general linear model fitted the data best: ∛ventricular volume (ml) = 1.096 + 0.094 × anterior horn width (mm) + 0.020 × thalamo-occipital distance (mm) with R = 0.831.

Conclusion: The volume of the lateral ventricles of infants with germinal matrix intraventricular haemorrhage can be estimated using 2-D cranial US images by application of a model.
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http://dx.doi.org/10.1007/s00247-019-04542-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6978291PMC
February 2020

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

Br J Clin Pharmacol 2020 01 3;86(1):75-84. Epub 2020 Jan 3.

Department of Neonatology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.

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.
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http://dx.doi.org/10.1111/bcp.14136DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6983510PMC
January 2020

Pharmacokinetics and short-term safety of the selective NOS inhibitor 2-iminobiotin in asphyxiated neonates treated with therapeutic hypothermia.

Pediatr Res 2020 03 2;87(4):689-696. Epub 2019 Oct 2.

Department of Neonatology, Wilhelmina Children's Hospital, University Medical Center Utrecht and Utrecht University, Utrecht, the Netherlands.

Background: Neonatal encephalopathy following perinatal asphyxia is a leading cause for neonatal death and disability, despite treatment with therapeutic hypothermia. 2-Iminobiotin is a promising neuroprotective agent additional to therapeutic hypothermia to improve the outcome of these neonates.

Methods: In an open-label study, pharmacokinetics and short-term safety of 2-iminobiotin were investigated in neonates treated with therapeutic hypothermia. Group A (n = 6) received four doses of 0.16 mg/kg intravenously q6h. Blood sampling for pharmacokinetic analysis and monitoring of vital signs for short-term safety analysis were performed. Data from group A was used to determine the dose for group B, aiming at an AUC of 4800 ng*h/mL.

Results: Exposure in group A was higher than targeted (median AUC 9522 ng*h/mL); subsequently, group B (n = 6) received eight doses of 0.08 mg/kg q6h (median AUC 4465 ng*h/mL). No changes in vital signs were observed and no adverse events related to 2-iminobiotin occurred.

Conclusion: This study indicates that 2-iminobiotin is well tolerated and not associated with any adverse events in neonates treated with therapeutic hypothermia after perinatal asphyxia. Target exposure was achieved with eight doses of 0.08 mg/kg q6h. Optimal duration of therapy for clinical efficacy needs to be determined in future clinical trials.
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http://dx.doi.org/10.1038/s41390-019-0587-1DOI Listing
March 2020

SUGAR-DIP trial: oral medication strategy versus insulin for diabetes in pregnancy, study protocol for a multicentre, open-label, non-inferiority, randomised controlled trial.

BMJ Open 2019 08 18;9(8):e029808. Epub 2019 Aug 18.

Department of Obstetrics and Gynaecology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.

Introduction: In women with gestational diabetes mellitus (GDM) requiring pharmacotherapy, insulin was the established first-line treatment. More recently, oral glucose lowering drugs (OGLDs) have gained popularity as a patient-friendly, less expensive and safe alternative. Monotherapy with metformin or glibenclamide (glyburide) is incorporated in several international guidelines. In women who do not reach sufficient glucose control with OGLD monotherapy, usually insulin is added, either with or without continuation of OGLDs. No reliable data from clinical trials, however, are available on the effectiveness of a treatment strategy using all three agents, metformin, glibenclamide and insulin, in a stepwise approach, compared with insulin-only therapy for improving pregnancy outcomes. In this trial, we aim to assess the clinical effectiveness, cost-effectiveness and patient experience of a stepwise combined OGLD treatment protocol, compared with conventional insulin-based therapy for GDM.

Methods: The SUGAR-DIP trial is an open-label, multicentre randomised controlled non-inferiority trial. Participants are women with GDM who do not reach target glycaemic control with modification of diet, between 16 and 34 weeks of gestation. Participants will be randomised to either treatment with OGLDs, starting with metformin and supplemented as needed with glibenclamide, or randomised to treatment with insulin. In women who do not reach target glycaemic control with combined metformin and glibenclamide, glibenclamide will be substituted with insulin, while continuing metformin. The primary outcome will be the incidence of large-for-gestational-age infants (birth weight >90th percentile). Secondary outcome measures are maternal diabetes-related endpoints, obstetric complications, neonatal complications and cost-effectiveness analysis. Outcomes will be analysed according to the intention-to-treat principle.

Ethics And Dissemination: The study protocol was approved by the Ethics Committee of the Utrecht University Medical Centre. Approval by the boards of management for all participating hospitals will be obtained. Trial results will be submitted for publication in peer-reviewed journals.

Trial Registration Number: NTR6134; Pre-results.
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http://dx.doi.org/10.1136/bmjopen-2019-029808DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6701578PMC
August 2019