Jacqueline Matis

Evaluation of interleukin-6 and soluble receptors of tumor necrosis factor for early diagnosis of neonatal infection.

OBJECTIVE To evaluate plasma levels of interleukin-6 (IL-6) and soluble tumor necrosis factor receptors (sTNF-R) 55 and 75 in neonates as a contribution to the early diagnosis of infection. STUDY DESIGN We prospectively measured IL-6 and sTNF-R 55 and sTNF-R 75 plasma levels in 157 newborn infants admitted to our regional neonatal center in a 3-month period and in cord blood of 131 newborn infants delivered in our obstetrics unit. C-reactive protein was sequentially determined after admission. Newborn infants were classified into four groups: group 0, not infected; group 1, possibly infected; group 2a, infected (culture positive), and group 2b, probably infected (culture negative). We looked for the optimal cutoff point of these parameters, using the receiver operating characteristics (ROC) curve. RESULTS IL-6 levels were significantly higher in group 2 (n = 11; median level, 250 pg/ml; range, 0 to 81,000), group 2b (n = 25; median level, 750 pg/ml; range, 0 to 180,000), and group 1 (n = 35; median level, 160 pg/ml; range 0 to 10,000), in comparison with group 0 (n = 217; median level, 0 pg/ml; range, 0 to 3400). A cutoff value of 100 pg/ml or greater obtained by the ROC method gives a sensitivity of 83.3% and a specificity of 90.3%. For inborn infants (n = 220) sampled at birth, sensitivity is 100% and specificity 92.3%. This high sensitivity persists until the twelfth hour of life. The sTNF-R 55 levels are significantly higher in group 2a (median, 12.0 ng/ml; range, 3.2 to 24.4). In group 2b (median, 7.0 ng/ml; range, 3.0 to 25.2), and in group 1 (median, 7.0 ng/ml; range, 2.5 to 18.9) than in group 0 (median, 3.9 ng/ml; range, 1.5 to 15.0), and with a cutoff value of 6 ng/ml, sensitivity is 75% and specificity 69%. The sTNF-R 75 levels are significantly higher in group 2a (median, 17.0 ng/ml; range, 7.2 to 48.8). In group 2b (median, 11.2 ng/ ml; range, (2.0 to 31.3), and in group 1 (median, 10.6 ng/ml; range, 2.0 to 33.0); than in group 0 (median, 7.0 ng/ml; range, 1 to 23.0). With a cutoff value of 9 ng/ ml, sensitivity is 80% and specificity 67%. Sensitivity of C-reactive protein is low initially but improves with time. Combining IL-6 with C-reactive protein provides the possibility of identifying the majority of infected infants in the postnatal period. CONCLUSION A plasma IL-6 level of 100 pg/ml or greater, obtained before the twelfth hour of life, appears to be an ideal marker for detecting early-onset neonatal infection with a high degree of sensitivity and specificity. After the twelfth hour, the combined determination of IL-6 and C-reactive protein may be equally useful. The sTNF-R levels appear to be less useful in the early diagnosis of infection because of their smaller magnitude of variation.

White matter damage and intraventricular hemorrhage in very preterm infants: the EPIPAGE study☆

OBJECTIVE To evaluate the prevalence of cranial ultrasound abnormalities in very preterm infants as a function of gestational age, plurality, intrauterine growth restriction, and death before discharge. STUDY DESIGN A prospective, population-based cohort of 2667 infants born between 22 and 32 weeks of gestation in 1997 in nine regions of France, transferred to a neonatal intensive care unit, for whom at least one cranial ultrasound scan was available. RESULTS The frequencies of white matter damage (WMD), major WMD, cystic periventricular leukomalacia (PVL), periventricular parenchymal hemorrhagic involvement, and intraventricular hemorrhage with ventricular dilatation were 21%, 8%, 5%, 3%, and 3%, respectively. The risk of WMD increased with decreasing gestational age. Mean age at diagnosis of cystic PVL was older for the most premature infants. Intraventricular hemorrhage with ventricular dilatation was associated with a higher risk of cystic PVL. Intrauterine growth restriction was not associated with a lower prevalence of cystic PVL. CONCLUSION The frequency of WMD is high in very preterm babies and is strongly related to gestational age. The incidence of cystic PVL did not differ between babies with intrauterine growth restriction and babies who were appropriate for gestational age.

Prenatal prediction of neonatal morbidity in survivors with congenital diaphragmatic hernia: a multicenter study

To investigate the value of the observed to expected fetal lung area to head circumference ratio (o/e LHR) and liver position in the prediction of neonatal morbidity in survivors with congenital diaphragmatic hernia (CDH).

Behavioral Outcome at 3 Years of Age in Very Preterm Infants: The EPIPAGE Study

OBJECTIVES. Our goal was to compare the prevalence of behavioral problems between very preterm children and term children at 3 years of age and examine the factors associated with behavioral problems in very preterm children. METHODS. We conducted a prospective population-based cohort study: the EPIPAGE (Étude Epidémiologique sur les Petits Ages Gestationnels) study. All infants born between 22 and 32 weeks of gestation in 9 regions of France in 1997 were included and compared with a control group of infants born at term. Sociodemographic status, obstetric, and neonatal data were collected at birth and in the neonatal units. At 3 years of age, the behavioral problems of 1228 very preterm singleton children without major neurodisabilities, and 447 term children were studied using the Strengths and Difficulties Questionnaire completed by the parents. RESULTS. Very preterm children were more likely than controls to have behavioral difficulties. Among very preterm children, several medical conditions were associated with a high total difficulty score: major neonatal cerebral lesions diagnosed by cranial ultrasonographic studies, hospitalization within the last year, poor health, and psychomotor delay. A high birth order and sociodemographic factors such as young maternal age and low educational level of the mother were also identified as risk factors for behavioral difficulties. The differences between very preterm children and controls remained significant after adjustment for sociodemographic characteristics, neonatal complications, and neurodevelopmental status, for a high total difficulties score, hyperactivity, conduct problems, and for peer problems. For emotional problems, the difference was at the limit of significance. CONCLUSIONS. Very preterm children have a higher risk of behavioral problems at 3 years of age compared with term-born children. Health and neurodevelopmental status of the child were significantly associated with behavioral difficulties.

Predictors of cerebral palsy in very preterm infants: the EPIPAGE prospective population-based cohort study.

Aim  The aim of this study was to assess the independent role of cerebral lesions on ultrasound scan, and several other neonatal and obstetric factors, as potential predictors of cerebral palsy (CP) in a large population‐based cohort of very preterm infants.

Predictors of the risk of cognitive deficiency in very preterm infants: the EPIPAGE prospective cohort

Aim:  To assess cerebral lesions and other medical as well as social characteristics as predictors of risk of mild and severe cognitive deficiencies in very preterm infants.

Diagnostic approach to neonatal hypotonia: retrospective study on 144 neonates.

The objectives of our study were to determine the actual frequency of the different disorders causing neonatal hypotonia and to assess the reliability of the first physical examination as well as the contribution of the main standard diagnostic tests. One hundred and forty-four infants diagnosed with neonatal hypotonia between January 1st 1999 and June 30th 2005 in our tertiary care facility were retrospectively included in the study. Perinatal history, clinical type of hypotonia, results of standard diagnostic tests, final diagnosis and outcome were abstracted from the original charts. A final diagnosis was reached in 120 cases. Central (cerebral) causes represented 82% of the elucidated cases, mostly hypoxic and hemorrhagic lesions of the brain (34%), chromosomal aberrations and syndromic disorders (26%) and brain malformations (12%). Peripheral (neuromuscular) causes were mainly represented by spinal muscular atrophy (6%) and myotonic dystrophy (4%). Positive predictive value of the initial clinical examination was higher in central type hypotonia. Neuroimaging, karyotype analysis and DNA-based tests were the most helpful diagnostic tools. These recent clinical data can be used to improve our strategy in investigating neonatal hypotonia and a diagnostic algorithm is proposed based on our findings.

Congenital hyperekplexia: five sporadic cases

We report fives sporadic cases of hyperekplexia or startle disease characterized by a highly exaggerated startle reflex and tonic attacks. Affected neonates suffer from prolonged periods of stiffness and are at risk for sudden death from apnea. An early diagnosis is needed. Sudden loud sounds, unexpected tactile stimuli or percussion at the base of the nose can also elicit excessive jerking or tonic attack. The diagnosis of hyperekplexia is a purely clinical one. A defect of the alpha1 subunit of inhibitory glycine receptor (GLRA1) has been observed in the dominant form with a mutation in the chromosome 5. Clonazepam is effective and decreases the severity of the symptoms. The disease tends to improve after infancy and the psychomotor development is normal. The major form of “hyperekplexia” should be considered whenever one is confronted with neonatal hypertonicity associated with paroxysmal tonic manifestations (without electroencephalography anomalies). Conclusion: the diagnosis of hyperekplexia should be evaluated in any neonate with tonic attacks without evident cause.

White matter damage and neonatal sepsis: authors’ reply

Sir, With great interest we read the article by Beaino et al. (1) on risk factors for cognitive deficiency in the very preterm infant. As confirmed in this study periventricular leukomalacia (PVL) is currently known to be an important risk factor for severe cognitive impairment. Maternal-foetal infections were not associated with either mild or severe cognitive deficiency, but the role of early and ⁄ or late onset sepsis was not evaluated in the multivariate analysis. We retrospectively compared data of all preterm infants diagnosed as having cystic PVL hospitalized at our tertiary care neonatal intensive care unit from 2004 to 2008 with matched controls (each PVL case with four control infants) for gestational age, birth weight, year of birth, and sex. Cranial ultrasound scans are routinely obtained in all preterm infants on days 1, 3, 5, and thereafter once a week in cases with pathological findings using a commercially available unit (Advanced Technology Laboratories Inc., Bothell, WA, USA). Twenty-two infants with diagnosis of cystic PVL with a median gestational age of 29 weeks (range 24–32 weeks) were compared to 88 controls. Diagnosis of first cysts occurred at median day 13 (range 4–26 days) and 77% of the infants had diagnosis of bilateral cystic PVL. Antenatal risk factors (chorioamnionitis, fever during labour, and preterm rupture of the membranes) and antibiotic therapy of the mother were associated with the presence of PVL (odds ratio (OR) 3.02, 95% confidence interval (CI) 1.07–8.54, p = 0.032 and OR 2.96, CI 95% 1–8.74, p = 0.044, respectively). Among the 22 cases of PVL eight infants had blood culture proven or clinical early onset sepsis (36%). Presence of early onset sepsis was significantly associated with PVL (OR 4, CI 95% 1.37–11.71, p < 0.01). When adjusted for presence of maternal risk factors and antibiotic therapy of the mother the association with sepsis was still significant (p = 0.035). Clinical factors associated with presence of white matter damage were cardiocirculatory symptoms (arterial hypotonia, tachyand bradycardia) (OR 2.74, CI 95% .98– 7.69, p < 0.05). Late onset sepsis was not associated with PVL (p = 0.25). The present analysis adds to a growing body of evidence suggesting a link between infection and white matter injury in the premature newborn. Several findings from human studies and animal models support the concept that a fetal exposure to inflammation triggers a prolonged neuroinflammatory response affecting the development of brain structure and function. Our results are limited by the small sample size but nevertheless confirm previous findings of bacterial infections in the early postnatal period being associated with a higher risk for white matter damage (2,3). Interestingly, Beaino et al. found no significant association of maternal-foetal infection with cognitive deficiency, but they did not link infection with white matter damage in their analysis. Further studies on the pathogenesis of white matter damage in the preterm infant are needed to evaluate the role of an either foetal or postnatal inflammatory response syndrome.

OC269: Prenatal prediction of neonatal morbidity in congenital diaphragmatic hernia: a multicenter study

Objectives: The fetal lung area to head circumference ratio and position of the liver are predictors of survival in isolated CDH. We aimed to investigate the value of the observed/expected LHR (o/e LHR) and position of the liver in the prediction of neonatal morbidity in survivors with congenital diaphragmatic hernia (CDH). Methods: Neonatal morbidity was recorded in 100 consecutive cases with prenatally diagnosed isolated CDH, who were expectantly managed in the prenatal period, were delivered after 30 weeks and survived until discharge from the hospital. Regression analysis was used to identify the significant predictors of morbidity, including prenatal and immediate neonatal findings. Results: The o/e LHR was the main significant predictor of the need for prosthetic patch repair, duration of assisted ventilation, need for supplemental oxygen at 28 days, and incidence of feeding problems. An additional independent prenatal predictor of the need for patch repair was the presence of fetal liver in the chest. Conclusions: In isolated CDH the prenatally assessed size of the contralateral lung is a significant predictor of the need for prosthetic patch repair, the functional consequences of impaired lung development and occurrence of feeding problems.