Timo R. de Haan

Effect of Treatment of Subclinical Neonatal Seizures Detected With aEEG: Randomized, Controlled Trial

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

Prognostic Tests in Term Neonates With Hypoxic-Ischemic Encephalopathy: A Systematic Review

BACKGROUND AND OBJECTIVE: Hypoxic-ischemic encephalopathy (HIE) after perinatal asphyxia in term neonates causes long-term neurologic sequelae or death. A reliable evidence-based prognosis is essential. The study goal was to investigate the prognostic value of currently used clinical tests in neonatal patients with perinatal asphyxia and HIE. METHODS: Searches were made on MEDLINE, Embase, Central, and CINAHL for studies occurring between January 1980 and November 2011. Studies were included if they (1) evaluated outcome in term infants with perinatal asphyxia and HIE, (2) evaluated prognostic tests, and (3) reported outcome at a minimal follow-up age of 18 months. Study selection, assessment of methodologic quality, and data extraction were performed by 3 independent reviewers. Pooled sensitivities and specificities of investigated tests were calculated when possible. RESULTS: Of the 259 relevant studies, 29 were included describing 13 prognostic tests conducted 1631 times in 1306 term neonates. A considerable heterogeneity was noted in test performance, cut-off values, and outcome measures. The most promising tests were amplitude-integrated electroencephalography (sensitivity 0.93, [95% confidence interval 0.78–0.98]; specificity 0.90 [0.60–0.98]), EEG (sensitivity 0.92 [0.66–0.99]; specificity 0.83 [0.64–0.93]), and visual evoked potentials (sensitivity 0.90 [0.74–0.97]; specificity 0.92 [0.68–0.98]). In imaging, diffusion weighted MRI performed best on specificity (0.89 [0.62–0.98]) and T1/T2-weighted MRI performed best on sensitivity (0.98 [0.80–1.00]). Magnetic resonance spectroscopy demonstrated a sensitivity of 0.75 (0.26–0.96) with poor specificity (0.58 [0.23–0.87]). CONCLUSIONS: This evidence suggests an important role for amplitude-integrated electroencephalography, EEG, visual evoked potentials, and diffusion weighted and conventional MRI. Given the heterogeneity in the tests’ performance and outcomes studied, well-designed large prospective studies are needed.

Neonatal Cerebral Sinovenous Thrombosis From Symptom to Outcome

Background and Purpose— Cerebral sinovenous thrombosis is a rare disease with severe neurological sequelae. The aim of this retrospective multicenter study was to investigate the clinical course, possible risk factors, and outcome of a cohort of neonatal patients with sinovenous thrombosis and, second, to estimate the incidence in The Netherlands. Methods— From January 1999 to March 2009, a review of all neonatal patients with sinovenous thrombosis from 6 tertiary neonatal intensive care units was performed. Population characteristics, clinical presentation, (prothrombotic) risk factors, neuroimaging, interventions, and neurodevelopment were evaluated. An estimated incidence was calculated based on the Netherlands Perinatal Registry. Results— Fifty-two neonates were included (39 boys) with a median gestational age of 39 weeks (range, 30 to 42 weeks; 5 preterm). An assisted or complicated delivery occurred in 32 of 52. Presenting symptoms developed at a median postnatal age of 1.5 days (range, 0 to 28 days) and consisted mainly of seizures (29 of 52). All sinovenous thrombosis cases were confirmed with MRI/MR venography. Multisinus thrombosis was most common followed by superior sagittal sinus thrombosis. FII G20210A mutation was present in 2 of 18 tested neonates (11%). Anticoagulation therapy (in 22 of 52) did not result in hemorrhagic complications. At follow-up (median age, 19 months; range, 3 to 72 months), moderate to severe neurological sequelae were present in 38%. The mortality was 10 of 52 (19%). A variable, although high yearly incidence of 1.4 to 12 per 100 000 term newborns was found. Conclusions— Neonatal sinovenous thrombosis is a multifactorial disease. The estimated incidence in The Netherlands seems higher than reported elsewhere.

Long-term outcome after fetal transfusion for hydrops associated with parvovirus B19 infection.

OBJECTIVE: To evaluate neurodevelopmental status of children treated with intrauterine red blood cell and platelet transfusion for fetal hydrops caused by parvovirus B19. METHODS: Maternal and neonatal records of all intrauterine transfusions for congenital parvovirus B19 infection in our center between 1997 and 2005 were reviewed. Congenital B19 virus infection was confirmed by the presence of parvovirus B19–specific immunoglobulin M or parvovirus B19 DNA in fetal blood samples. All children underwent a general pediatric and neurological examination. Primary outcome measure was neurodevelopmental status (developmental index by Bayley Scales of Infant Development or Snijders-Oomen test). Secondary outcome measure was general health status of surviving children. RESULTS: A total of 25 intrauterine transfusions were performed in 24 hydropic fetuses. Median fetal hemoglobin concentration, platelet count, and blood pH before intrauterine transfusions were 4.5 g/dL (range 2.4–11.4 g/dL), 79×109/L (range 37–238×109/L) and 7.36 (range 7.31–7.51), respectively. Sixteen survivors aged 6 months to 8 years were included in the follow-up study. Eleven children (68%) were normal, and 5 children (32%) demonstrated a delayed psychomotor development with an suboptimal neurological examination (mild delay n=3, severe delay n=2). Neurodevelopmental status did not correlate with pre-intrauterine transfusion hemoglobin, platelet, or blood pH values. Growth and general health status were normal in all. Two children had minor congenital defects. CONCLUSION: Neurodevelopmental status was abnormal in 5 of 16 survivors and was not related to the severity of fetal anemia and acidemia. We hypothesize that fetal parvovirus B19 infection may induce central nervous system damage. LEVEL OF EVIDENCE: III

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

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

A simple quantitative method analysing amikacin, gentamicin, and vancomycin levels in human newborn plasma using ion-pair liquid chromatography/tandem mass spectrometry and its applicability to a clinical study

Neuroprotective controlled therapeutic hypothermia is the standard of care for newborns suffering perinatal asphyxia. Antibiotic drugs, such as amikacin, gentamicin, and vancomycin are frequently administered during controlled hypothermia, which possibly alters their pharmacokinetic (PK) and pharmacodynamic (PD) profiles. In order to examine this effect an LC-MS/MS method for the simultaneous quantification of amikacin, the major gentamicin components (gentamicin C, C1a and C2), and vancomycin in plasma was developed. In 25μL plasma proteins were precipitated with trichloroacetic acid (TCA) and detection of the components was achieved using ion-pair reversed phase chromatography coupled with electrospray ionization tandem mass spectrometry. The chromatographic runtime was 7.5min per sample. Calibration standards were prepared over a range of 0.3-50mgL(-1) for amikacin and gentamicin and 1.0-100mgL(-1) for vancomycin. At LLOQ accuracy was between 103 and 120% and imprecision was less than 19%. For concentrations above LLOQ accuracy ranged from 98% to 102% and imprecision was less than 6%. Process efficiency, ionization efficiency, and recovery were acceptable. Samples and stock solutions were stable during the time periods and at the different temperatures examined. The applicability of the method was shown by analysing plasma samples from 3 neonatal patients. The developed method allows accurate and precise simultaneous quantification of amikacin, gentamicin, and vancomycin in a small volume (25μL) of plasma.

Disturbance of Cerebral Neuronal Migration following Congenital Parvovirus B19 Infection

Objective: We describe the clinical course of an infant who presented with severe fetal anemia and fetal hydrops following congenital parvovirus B19 infection before 16 gestational weeks. The fetus was treated by cordocentesis and intrauterine transfusion at 18 weeks. Results: The infant demonstrated mild unilateral ventriculomegaly on antenatal magnetic resonance imaging, and polymicrogyria and heterotopia on postnatal magnetic resonance imaging. Conclusion: This adds to the evidence in recent literature of central nervous system damage associated with congenital parvovirus B19 infection.

Maternal allopurinol administration during suspected fetal hypoxia: a novel neuroprotective intervention? A multicentre randomised placebo controlled trial

Objective To determine whether maternal allopurinol treatment during suspected fetal hypoxia would reduce the release of biomarkers associated with neonatal brain damage. Design A randomised double-blind placebo controlled multicentre trial. Patients We studied women in labour at term with clinical indices of fetal hypoxia, prompting immediate delivery. Setting Delivery rooms of 11 Dutch hospitals. Intervention When immediate delivery was foreseen based on suspected fetal hypoxia, women were allocated to receive allopurinol 500 mg intravenous (ALLO) or placebo intravenous (CONT). Main outcome measures Primary endpoint was the difference in cord S100ß, a tissue-specific biomarker for brain damage. Results 222 women were randomised to receive allopurinol (ALLO, n=111) or placebo (CONT, n=111). Cord S100ß was not significantly different between the two groups: 44.5 pg/mL (IQR 20.2–71.4) in the ALLO group versus 54.9 pg/mL (IQR 26.8–94.7) in the CONT group (difference in median −7.69 (95% CI −24.9 to 9.52)). Post hoc subgroup analysis showed a potential treatment effect of allopurinol on the proportion of infants with a cord S100ß value above the 75th percentile in girls (ALLO n=5 (12%) vs CONT n=10 (31%); risk ratio (RR) 0.37 (95% CI 0.14 to 0.99)) but not in boys (ALLO n=18 (32%) vs CONT n=15 (25%); RR 1.4 (95% CI 0.84 to 2.3)). Also, cord neuroketal levels were significantly lower in girls treated with allopurinol as compared with placebo treated girls: 18.0 pg/mL (95% CI 12.1 to 26.9) in the ALLO group versus 32.2 pg/mL (95% CI 22.7 to 45.7) in the CONT group (geometric mean difference −16.4 (95% CI −24.6 to −1.64)). Conclusions Maternal treatment with allopurinol during fetal hypoxia did not significantly lower neuronal damage markers in cord blood. Post hoc analysis revealed a potential beneficial treatment effect in girls. Trial registration number NCT00189007, Dutch Trial Register NTR1383.

Parvovirus B19 Infection in Pregnancy Studied by Maternal Viral Load and Immune Responses

Objectives: Facilitate risk assessment of vital complications in fetuses of pregnancies affected by acute parvovirus B19 (B19V) infection. Design: Study of the natural course of maternal B19V infection in four cases, from early pregnancy on. Setting: University Medical Center in the Netherlands. Population: Pregnant mothers attending obstetric services. Methods: Serial measurements of the maternal and fetal or neonatal viral load and antibody responses. Main Outcome Measures: Maternal and fetal/neonatal serum B19V viral DNA load and specific IgM and IgG antibodies in maternal serum. Results: Peak viral load levels occurred within 1 week after maternal infection and peak IgM levels were observed 1 week after the peak viral load levels. Approximation of IgG and IgM ratios usually took place 4 weeks after infection. Vertical transmission occurred 1–3 weeks after maternal infection, suggesting that fetal infection occurs during the maternal peak viral load. Conclusions: Maternal B19V DNA load levels and IgM responses are useful to estimate the risk of parvovirus B19-associated fetal complications. The maternal peak viral load directly precedes the onset of fetal infection and may be used to indicate the stage of intrauterine B19V infection.

Fetal stroke and congenital parvovirus B19 infection complicated by activated protein C resistance

UNLABELLED Parvovirus B19 infection in gestation has been associated with severe fetal complications such as anaemia, hydrops and fetal demise. Fetal infection in the first trimester poses the greatest risk for these complications, but infection during the third trimester is more common than previously appreciated and can be associated with severe complications, i.e. fetal death, in the absence of hydrops or classical clinical symptoms. Parvovirus B19 infection has been associated with vasculitis and pathological changes in the central nervous system, which may cause stroke. We report a newborn infant with a rare combination of a recent central nervous system infection with parvovirus B19 and a factor V Leiden mutation, who developed fetal stroke. CONCLUSION Factor V Leiden mutation leads to activated protein C resistance and increases the risk of thromboembolism. Thromboembolism occurs rarely in newborns with activated protein C resistance, but can be precipitated by dehydration, asphyxia and infection. Although parvovirus B19 infection of the central nervous system may be a precipitant in neonatal and/or fetal stroke, it can also cause stroke independent of a thrombophilic mutation. In this case, both causative factors may have coincided.