Associations between neural injury markers of intrauterine growth-restricted infants and neurodevelopment at 2 years of age.

Objectives: The aim of this study was to evaluate the relationships between brain injury biomarkers in intrauterine growth-restricted (IUGR) infants (S100B and neuron-specific enolase (NSE)) and neurodevelopment at 2 years of age. Methods: This prospective case-control study was a cooperative effort among Spanish Maternal and Child Health Network (Retic SAMID) hospitals. At inclusion, biometry for estimated fetal weight and feto-placental Doppler variables were measured for each infant. Maternal venous blood and fetal umbilical arterial blood samples were collected at the time of delivery and neural injury markers S100B and NSE concentrations were measured. Neurodevelopment was evaluated at 2 years of age using the Bayley Scales of Infant and Toddler Development, third edition (Bayley-III). Results: Fifty six pregnancies were included. Thirty-one infants were classified as IUGR and 25 as non-IUGR. Neurodevelopmental evaluation at 2 years of age indicated that there were no between-group differences for any of the tests. For all patients in both groups, we found statistically significant inverse relationships between the concentrations of NSE in the cord blood and the results of the cognitive test (r = -271, p = .042), fine motor subtest (r = -280, p = .036), and social-emotional test (r = -349, p = .015). We also found statistically significant differences between the concentrations of S100B in the cord blood and the results of the cognitive test (r = -306, p = .022) and expressive communication subtest (r = -304, p = .023). For the IUGR group, we found a significant inverse relationship between the concentrations of S100B in the maternal serum and the results of adaptive behavior test (p < .05). In the non-IUGR group, we found statistically significant inverse relationships between the concentration of NSE in the cord blood and the results of the fine motor subtest (r = -446, p = .025) and social-emotional test (r = -489, p = .021). The difference between the concentration of S100B in the cord blood and the language composite score was also statistically significant (p = .038). Conclusions: At 2 years of age, the concentrations of NSE and S100B were higher in the non-IUGR and IUGR groups with the worst scores for some areas of neurodevelopmental evaluation. The value of these biomarkers for prognostic neurodevelopmental use requires further investigation for both non-IUGR and IUGR infants.

Duración de la reanimación en neonatos con Apgar a los 10 min menor de 3 en la era de la hipotermia / Duration of resuscitation in neonates with Apgar scores at 10 minutes of less than 3 in the hypothermia era

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Algoritmo para la asignación etiológica de la prematuridad / Algorithm for an etiological classification of prematurity

Ante la dificultad para clasificar etiológicamente la prematuridad, en la práctica se ha impuesto una división en 3 subtipos según la presentación clínica: prematuridad médicamente indicada, rotura prematura de membranas (RPM) y espontánea o idiopática. Sin embargo, esta categorización es discutible, resulta poco precisa y admite criterios diversos a la hora de su aplicación. Objetivo: Elaborar una clasificación causal de la prematuridad y diseñar un sistema que facilite la asignación de cada caso concreto en el período perinatal. Métodos: Revisión sistematizada de la literatura médica, técnica cualitativa de consenso mediante grupo nominal, y cuantitativa, mediante estudio piloto con la versión inicial del algoritmo. Resultados: Se elaboró una clasificación que estableció una división general entre causa «próxima principal» y «causas asociadas», lo que permitió incluir concausas e, incluso, factores de riesgo más remotos. La causa principal incluyó 7 grandes categorías: inflamatorias (RPM y afines), vasculares (restricción del crecimiento intrauterino y afines), maternas locales, maternas generales, enfermedad fetal, pérdida de bienestar fetal e idiopáticas. La prematuridad de causa electiva o «por indicación médica» se estableció como categoría previa e independiente y, por tanto, compatible con las otras causas consideradas. Para facilitar el establecimiento de la causa principal, se diseñó un algoritmo con formato de diagrama de flujo unidireccional. Conclusiones: Se propone una clasificación pragmática de la prematuridad que facilite un cierto grado de precisión y la concordancia entre los clínicos (AU)

Due to the difficulty in classifying the etiology of preterm birth, it has been dicided into three subtypes according to its clinical presentation: medically indicated, ruptured membranes, and spontaneous or idiopathic. Nevertheless, this classification is controversial, imprecise and can result in multiple interpretations when applied. Objective: To design an etiologically based classification of preterm birth, and to design a system to easily assign each case during the perinatal period. Methods: Review of literature, qualitative analysis using consensus methods through nominal group technique, and quantitative analysis of a pilot study using a first version of the algorithm. Results: A classification is made to establish a general division between the “primary cause” and “associated causes” of preterm birth, that allows remote causes or risk factors to be included. The primary cause includes seven categories: inflammatory (ruptured membranes and related); vascular (intrauterine growth restriction and related); maternal–local; maternal–systemic; fetal pathology; fetal distress; idiopathic. The medically indicated preterm birth is defined as a previous or independent category and so is compatible with the other, previously mentioned causes. An algorithm was designed to make it easier to classify the primary cause of preterm birth usinf a flowchart. Conclusions: A pragmatic classification of preterm birth is proposed that may help to achieve better precision and agreement between clinicians (AU)

[Reduced postnatal growth in very low birth weight newborns with GE < or = 32 weeks in Spain]. / Restricción posnatal del crecimiento en recién nacidos españoles de muy bajo peso con edad gestacional menor o igual a 32 semanas.

AIM: To analyze postnatal growth restriction in a cohort of very low birth weight (VLBW) infants with gestational age < or = 32 weeks in 55 Spanish neonatal units (SEN 1500 Network) during 2002 and 2003. METHODS: Weight, length and head circumference were recorded at birth, and at discharge. Weight was also recorded at 28 days postnatal, and 36 weeks of postmenstrual age. Growth restriction was measured as the shift in weight z score from birth to 28th day. RESULTS: The study included 2317 VLBW infants. Weight z score at birth, 28 days, 36 weeks of postmenstrual age and discharge were: -0.66 +/- 1.3, -2.54 +/- 1.35, -3.12 +/- 1.7, -1.56 +/- 1.1, respectively. Length z score at birth and at discharge were: -0.88 +/- 1.8, and -1.97 +/- 1.56. Head circumference z score at birth and at discharge: -0.83 +/- 1.87, and -0.60 +/- 1.96. Prenatal steroids, gestational age, place of birth, type of hospital, CRIB score, symptomatic patent ductus arteriosus and late-onset bacterial sepsis were related with the shift in weight z score at 28 days (multiple linear regression), but explained very little (14 %) of his change. Weight and length at discharge were under the 10th percentile in 77 % and 80 % of the infants, respectively. CONCLUSIONS: VLBW infants < or = 32 GA suffer postnatal growth restriction with respect to intrauterine growth pattern, which is more relevant in the first 28 days of life, in patients with more severe illnesses, and differs among neonatal units. Perinatal and neonatal items evaluated are poorly related with restriction.

Restricción posnatal del crecimiento en recién nacidos españoles de muy bajo peso con edad gestacional menor o igual a 32 semanas / Reduced postnatal growth in very low birth weight newborns with GE <= 32weeks in Spain

Objetivo: Analizar la restricción posnatal del crecimiento en una cohorte de recién nacidos de muy bajo peso (RNMBP) y de no más de 32 semanas de gestación de 55 unidades de neonatología españolas (SEN 1500). Métodos: Se estudiaron peso, longitud y perímetro craneal al nacer y en el momento del alta. El peso se registró también a los 28 días de vida y 36 semanas de edad posmenstrual. Se analizó la relación entre restricción de crecimiento y datos perinatales y neonatales. Resultados: Se incluyeron 2.317 niños. La puntuación Z de peso al nacer, a los 28 días, a las 36 semanas de edad posmenstrual y al alta fue, respectivamente, ­0,66 ± 1,3, ­2,54 ± 1,35, ­3,12 ± 1,7, ­1,56 ± 1,1. La puntuación Z de longitud al nacer y al alta fue ­0,88 ± 1,8 y ­1,97 ± 1,56, respectivamente; la puntuación Z del perímetro craneal al nacer fue ­0,83 ± 1,87 y en el momento del alta ­0,60 ± 1,96. Los factores relacionados con el grado de restricción de peso a los 28 días fueron: corticoides prenatales, edad gestacional, lugar de nacimiento, tipo de hospital, puntuación CRIB, ductus arterioso persistente sintomático y sepsis tardía. Estos factores sólo explicaron el 14 % de la variabilidad del grado de restricción. El peso y la longitud al alta fueron inferiores a P10 en el 77 % y el 80 % de los RNMBP, respectivamente. Conclusiones: Los RNMBP de no más de 32 semanas de gestación durante su estancia en las unidades de neonatología sufren una "restricción de crecimiento" respecto al patrón intrauterino. Esta restricción ocurre sobre todo en los primeros 28 días de vida y es diferente en distintas unidades españolas. Las variables estudiadas explican en escasa medida este fenómeno (AU)

Aim: To analyze postnatal growth restriction in a cohort of very low birth weight (VLBW) infants with gestational age <= 32 weeks in 55 Spanish neonatal units (SEN 1500 Network) during 2002 and 2003. Methods: Weight, length and head circumference were recorded at birth, and at discharge. Weight was also recorded at 28 days postnatal, and 36 weeks of postmenstrual age. Growth restriction was measured as the shift in weight z score from birth to 28th day. Results: The study included 2317 VLBW infants. Weight z score at birth, 28 days, 36 weeks of postmenstrual age and discharge were: ­0.66 ± 1.3, ­2.54 ± 1.35, ­3.12 ± 1.7, ­1.56 ± 1.1, respectively. Length z score at birth and at discharge were: ­0.88 ± 1.8, and ­1.97 ± 1.56. Head circumference z score at birth and at discharge: ­0.83 ± 1.87, and ­0.60 ± 1.96. Prenatal steroids, gestational age, place of birth, type of hospital, CRIB score, symptomatic patent ductus arteriosus and late-onset bacterial sepsis were related with the shift in weight z score at 28 days (multiple linear regression), but explained very little (14 %) of his change. Weight and length at discharge were under the 10th percentile in 77 % and 80 % of the infants, respectively. Conclusions: VLBW infants <= 32 GA suffer postnatal growth restriction with respect to intrauterine growth pattern, which is more relevant in the first 28 days of life, in patients with more severe illnesses, and differs among neonatal units. Perinatal and neonatal items evaluated are poorly related with restriction (AU)

Reanimación cardiopulmonar avanzada neonatal: ¿hay datos para actuar de forma diferente frente al recién nacido extremadamente prematuro? / Advanced cardiopulmonary resuscitation in the newborn: Are there data to justify adopting different protocols for the extremely premature neonate

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Cerebrospinal fluid leucocyte counts in healthy neonates.

OBJECTIVES: To determine the cerebrospinal fluid (CSF) white blood cell (WBC) count of normal term neonates, and compare the CSF WBC profile of normal and symptomatic infants without infection of the central nervous system (CNS). METHOD: Neonates were included if (a) they were at risk of congenital Toxoplasma infection and had undergone a lumbar puncture to assess CNS involvement, and (b) serial specific serum IgG and IgM determinations had ruled out congenital infection. According to neonatal chart reviews, 30 consecutive patients without CNS infection were classified as normal (absolutely asymptomatic) or symptomatic (any kind of symptoms). RESULTS: CSF WBC count was higher in 11 symptomatic (7/mm(3), 0-30/mm(3)) than in 19 normal (1/mm(3), 0-5/mm(3)) neonates (p<0.01). CONCLUSION: Normal neonatal CSF contains up to 5 WBCs/mm(3). Mild pleocytosis can be found in symptomatic infants without CNS infection.

[Clinical progress of neonatal non-ketotic hyperglycinemia under treatment]. / Evolución de la hiperglicinemia no cetósica neonatal en tratamiento.

INTRODUCTION: Non-ketotic hyperglycinemia is a congenital error in the breakdown of glycine. The most common type is the classical neonatal form, which begins at the age of a few days with symptoms of lethargy, hypotonia, myoclonia, convulsions, apneas and, frequently, ends in death. Survivors usually develop intractable epilepsy and mental retardation. There is no effective treatment for this condition, but trials have been carried out with a therapy that diminishes the levels of glycine, benzoate (BZ), and another that blocks the excitatory effect in N-methyl-D-aspartate receptors: dextromethorphan (DTM). CASE REPORT: We report on the progress of a classical neonatal case, which began at the age of a few hours with hypotonia and stupor, without myoclonias or seizures, but with a suppression wave trace on the electroencephalogram (EEG). Cerebrospinal fluid (CSF) showed glycine levels of 141 micromol/L (the normal level is 6.66 +/- 2.66 micromol/L), with a CSF/plasma ratio of 0.19 (the normal ratio is < 0.02). Treatment was started on the thirteenth day with BZ and DTM, and alertness and eye fixation improved in just three days; at the same time the EEG readings become normal. The glycine level in plasma returned to normal at two months and that in CSF was considerably reduced, although with CSF/plasma levels that were still high. At present the patient is 4 years old, has never had convulsions, EEG results have always been normal, and continues with BZ, DTM, carnitine and diet. The patient has presented a high degree of hypermotoric behaviour, but is currently more attentive and more sociable, has been walking from the age of 35 months and has a quotient in the different areas of development of 40-50. CONCLUSIONS: The clinical progress made by our patient could be said to be anything but negligible, and we therefore recommend that treatment should be started as early as possible after diagnosis.

Evolución de la hiperglicinemia no cetósica neonatal en tratamiento / Clinical progress of neonatal non-ketotic hyperglycinemia under treatment

Introducción. La hiperglicinemia no cetósica es un error congénito de la degradación de la glicina. La forma más frecuente es la clásica neonatal, que se inicia a los pocos días con letargia, hipotonía, mioclonías, convulsiones, apneas y, con frecuencia, muerte. Los que sobreviven suelen desarrollar epilepsia rebelde y retraso mental. No existe tratamiento efectivo, pero se ha ensayado una terapia que disminuye la concentración de glicina, el benzoato (BZ), y otra que bloquea el efecto excitatorio en los receptores N-metil-Daspartato: el dextrometorfano (DTM). Caso clínico. Presentamos la evolución de un caso clásico neonatal, que debutó a las pocas horas con hipotonía y estupor, sin mioclonías ni crisis, pero con trazado onda-supresión en el electroencefalograma (EEG). El líquido cefalorraquídeo (LCR) mostró una concentración de glicina de 141 µmol/L (la normal es 6,66 ñ 2,66 µmol/L), con un cociente LCR/ plasma de 0,19 (el cociente normal es inferior a 0,02). Se inició el tratamiento al decimotercer día con BZ y DTM, y el estado de alerta y fijación ocular mejoró en sólo tres días; al mismo tiempo, se normalizó el EEG. La glicina en el plasma se normalizó ya a los dos meses, y en el LCR se redujo considerablemente, aunque con proporciones LCR/plasma todavía altas. Actualmente, el paciente tiene 4 años, nunca ha tenido convulsiones, los EEG siempre han sido normales y sigue con BZ, DTM, carnitina y dieta. Ha presentado una gran hipermotricidad, pero, actualmente está más atento y es más sociable, camina desde los 35 meses y tiene un cociente en las distintas áreas del desarrollo de 40-50. Conclusión. Parece aceptable la evolución clínica seguida por nuestro paciente, por lo que recomendamos siempre instaurar precozmente el tratamiento tras este diagnóstico (AU)

Introduction. Non-ketotic hyperglycinemia is a congenital error in the breakdown of glycine. The most common type is the classical neonatal form, which begins at the age of a few days with symptoms of lethargy, hypotonia, myoclonia, convulsions, apneas and, frequently, ends in death. Survivors usually develop intractable epilepsy and mental retardation. There is no effective treatment for this condition, but trials have been carried out with a therapy that diminishes the levels of glycine, benzoate (BZ), and another that blocks the excitatory effect in N-methyl-D-aspartate receptors: dextromethorphan (DTM). Case report. We report on the progress of a classical neonatal case, which began at the age of a few hours with hypotonia and stupor, without myoclonias or seizures, but with a suppression wave trace on the electroencephalogram (EEG). Cerebrospinal fluid (CSF) showed glycine levels of 141 µmol/L (the normal level is 6.66 ± 2.66 µmol/L), with a CSF/plasma ratio of 0.19 (the normal ratio is < 0.02). Treatment was started on the thirteenth day with BZ and DTM, and alertness and eye fixation improved in just three days; at the same time the EEG readings become normal. The glycine level in plasma returned to normal at two months and that in CSF was considerably reduced, although with CSF/plasma levels that were still high. At present the patient is 4 years old, has never had convulsions, EEG results have always been normal, and continues with BZ, DTM, carnitine and diet. The patient has presented a high degree of hypermotoric behaviour, but is currently more attentive and more sociable, has been walking from the age of 35 months and has a quotient in the different areas of development of 40-50. Conclusions. The clinical progress made by our patient could be said to be anything but negligible, and we therefore recommend that treatment should be started as early as possible after diagnosis (AU)

[Congenital adrenal hyperplasia: an association with increased fetal nuchal translucency]. / Hiperplasia suprarrenal congénita: asociación con translucencia nucal fetal aumentada.

A neonate with increased nuchal translucency and congenital adrenal hyperplasia is described. The possible interferences in hormone assays when values are much higher than the average assay range are also discussed.

Hiperplasia suprarrenal congénita: asociación con translucencia nucal fetal aumentada / Congenital adrenal hyperplasia: an association with increased fetal nuchal translucency

Se presenta el caso de un recién nacido con hiperplasia suprarrenal congénita y aumento de la translucencia nucal fetal. También se describen las posibles interferencias que pueden encontrarse en las determinaciones hormonales cuando los valores de la misma superan ampliamente el rango habitual de los ensayos (AU)

Sobre recomendaciones, protocolos y guías clínicas / On recommendations, protocols and clinical guidelines

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Interleukin-6 in the cerebrospinal fluid after perinatal asphyxia is related to early and late neurological manifestations.

OBJECTIVES: To investigate if the concentration of interleukin-6 (IL-6) in the cerebrospinal fluid (CSF) is affected by perinatal asphyxia, and to examine the relation of IL-6 levels in the CSF to the severity of hypoxic-ischemic encephalopathy (HIE), to brain damage, and to the neurological outcome. METHODS: Asphyxiated term neonates were included. Cerebrospinal fluid IL-6 was measured by a sensitive enzyme-linked immunosorbent assay. RESULTS: Twenty neonates were studied: 3 had no HIE, 5 had stage 1, 6 had stage 2, and 6 had stage 3. CSF IL-6 levels (8 to 90 hours of life) were higher in neonates with HIE stage 3 (range, 65 to 2250 pg/mL) when compared with neonates with HIE stage 0 to 2 (<2 pg/mL in 12 neonates, 10 pg/mL in 1). According to neuroimaging techniques and/or pathological examination, 14 neonates were normal, and 5 showed signs of brain damage; 1 was not classified. CSF IL-6 levels were significantly higher in neonates with signs of brain damage. Finally, 5 neonates had adverse outcomes (4 died, 1 had cerebral palsy), 2 had mild motor impairment, and 13 had normal outcomes. CSF IL-6 levels were higher in neonates with adverse outcomes (range, 65 to 2250 pg/mL) compared with neonates with favorable outcomes. CONCLUSION: The magnitude of IL-6 response in the CSF after perinatal asphyxia is related to the severity of neonatal HIE, to brain damage, and to the neurological outcome. Our results suggest that IL-6 might play a role in neonatal hypoxic-ischemic brain damage.

Multiple organ involvement in perinatal asphyxia.

OBJECTIVES: (1) To evaluate the frequency and spectrum of severity of multisystem dysfunction after perinatal asphyxia and (2) to analyze the relationship between the clinical and biochemical markers of perinatal asphyxia and multiorgan involvement. STUDY DESIGN: Seventy-two consecutive term newborn infants with perinatal asphyxia were studied prospectively. Systematic neurologic, renal, pulmonary, cardiac, and gastrointestinal evaluations were performed. Involvement of each organ was classified as moderate or severe. RESULTS: Involvement of one or more organs occurred in 82% of the infants; the central nervous system (CNS) was most frequently involved (72%). Severe CNS injury (7 infants) always occurred with involvement of other organs, although moderate CNS involvement was isolated in 14 infants. Renal involvement occurred in 42%, pulmonary in 26%, cardiac in 29%, and gastrointestinal in 29% of the infants; 15% neonates had renal failure and 19% had respiratory failure. The Apgar scores at 1 and 5 minutes were the only perinatal factors related to the number of organs involved and the severity of involvement; the Apgar score at 5 minutes had the stronger independent association. No relationship or organ dysfunction was found with the umbilical cord arterial blood pH, meconium-stained amniotic fluid, umbilical cord abnormalities, presentation, or type of delivery. CONCLUSIONS: Our findings indicate that the Apgar score at 5 minutes, in infants who have other criteria for asphyxia, is the perinatal marker that may best identify infants at risk of organ dysfunction.

Cerebrospinal fluid beta 2-microglobulin in neonates with central nervous system infections.

Beta 2-microglobulin (beta 2m) determination in CSF of 72 neonates who underwent a spinal tap as part of a sepsis or meningo-encephalitis workup was performed to evaluate the usefulness of this test in the diagnosis of CNS infections. Beta 2m was measured by enzyme immunoassay. Sixty neonates had sterile culture and normal neurological status at discharge. Twelve infants had CNS infections: 8 bacterial meningitis, 3 TORCH infections (T = toxoplasmosis, O = others, R = rubella, C = cytomegalovirus and H = herpes simplex) and 1 viral meningitis. Neonates with CNS infection exhibited significantly higher CSF beta 2m levels compared to neonates with sterile culture (6.24 +/- 2.66 vs 1.74 +/- 0.5 mg/l; P < 0.0001). CSF beta 2m levels did not correlate with the white cell count, total protein concentration or glucose level in CSF. When serum and CSF levels were measured simultaneously, the CSF beta 2m level was significantly higher than the corresponding serum level in patients with CNS infection (6.98 +/- 2.5 vs 3.2 +/- 0.25 mg/l; P < 0.01). Sensitivity, specificity, and predictive values were estimated for different cut-off points. The best operational diagnostic cut-off value was 2.25 mg/l. Receiver operating characteristic curve analysis showed an appropriate trade-off between specificity and sensitivity and indicated that CSF beta 2m was accurate in distinguishing between neonates with and without CNS infection. Conclusion. CSF beta 2m may be a useful ancillary tool in neonates when CNS infection is suspected.

Mononucleosis caused by Epstein-Barr virus and cytomegalovirus in children: a comparative study of 124 cases.

We present 124 children who had mononucleosis. The patients were selected according to strict clinical features. Twenty (16.1%) of the 124 children were proved to have cytomegalovirus mononucleosis and 104 (83.8%) children had Epstein-Barr virus mononucleosis. The symptoms were similar in both groups. Significant differences were found only for the presence of cervical lymphadenopathy, which was more frequent in the Epstein-Barr group (83.2%) compared with the cytomegalovirus group (75%). Fever was the most frequent symptom in both groups. Cytomegalovirus mononucleosis was significantly more frequent in children younger than 4 years.