Review shows that using surfactant a number of times or as a vehicle for budesonide may reduce the risk of bronchopulmonary dysplasia.

AIM: Bronchopulmonary dysplasia (BPD) remains the most common respiratory morbidity in immature infants. This review describes the diagnosis of BPD has evolved and summarises the therapeutic approaches that have made it possible to limit the incidence of BPD. METHOD: We reviewed the literature from the first definition of BPD by Northway in 1967 to the surfactant treatment policies that are currently in use, drawing on more than 50 papers up to 2017. RESULTS: Our review showed that improvements in neonatal survival have been associated with an increased risk of severe BPD, significant levels of long-term morbidity and the increased use of healthcare resources. These issues have encouraged researchers to explore potential new treatments that limit the incidence of BPD. Repeated surfactant instillation and the use of surfactant as a vehicle for budesonide are promising strategies for alleviating the burden of chronic lung disease. Ongoing research on surfactant or stem cell therapy may further improve the respiratory prognosis for prematurely born children. CONCLUSION: Considerable research has been carried out into the increase in BPD, which has resulted from improvements in neonatal survival. Key areas of research include repeated surfactant administration, using surfactant as a vehicle for budesonide and stem cell therapy.

Periventricular leukomalacia and mode of delivery in twins under 1500 g.

BACKGROUND: The optimal mode of delivery in twin gestations remains undefined, particularly for twins weighing less than 1500 g. OBJECTIVE: To evaluate the impact of the mode of delivery on neonatal outcome in twins below 1500 g. MATERIALS AND METHODS: In this multicenter cohort study during 1999, 66 sets of twins born in hospital and weighing below 1500 g formed our study group. Antenatal and neonatal parameters and their relationship to mode of delivery were studied, based on a factor analysis. Analysis of covariance was used to assess the effect of the mode of delivery on postnatal factors, with antenatal parameters used as covariates. RESULTS: Statistical analysis showed that infants delivered vaginally had significantly more periventricular leukomalacia than those children delivered by Cesarean section (p = 0.03). The estimated odds for leukomalacia were higher in the vaginal than in the Cesarean group when adjusted for covariates (OR = 4.7; 95% CI = 1.0, 25.15). CONCLUSION: Routine Cesarean section should be recommended in twin gestations with infants weighing less than 1500 g, regardless of gestational age or fetal presentation.

Perinatal factors affecting survival and survival without disability of extreme premature infants at two years of age.

OBJECTIVE: To study obstetrical factors leading to very preterm delivery (between 24 and 28 weeks) and to relate these factors to neonatal outcome and psychomotor development at two years. STUDY DESIGN: Among 144 infants born alive before 28 weeks of gestation at a single perinatal center between January 1993 and December 1996, we analyzed the influence on neonatal outcome and on psychomotor development at 24 months of a variety of perinatal and neonatal factors. Psychomotor development at two years was classified as: normal, borderline, or moderately or severely handicapped. RESULTS: During the study period, 114 women delivered live infants before 28 weeks' gestation: 87 singletons, 25 sets of twins, 1 set of triplets and 1 set of quadruplets. All 144 live-born infants received neonatal resuscitation: 50 died before discharge. At two years of age, 6 of the 94 survivors were lost to follow-up. Assessments of the psychomotor development of the other 88 was normal for 52%; borderline for 20%, moderately handicapped for 20%, and severely handicapped for 8%. Multivariate analysis found that two factors affected survival: birthweight and fetal heart rate. (The 42% of infants with a birthweight below 700 g survived versus 83% above 900 g, P<0.001, OR=5.2, 95% CI (confidence interval) [2.4-11.2].) CONCLUSION: These data show the influence of perinatal factors on the outcome of very preterm infants; birthweight and fetal heart rate are strongly correlated with survival. Gestational age is a good predictor of psychomotor development at two years.

Late-onset cystic periventricular leukomalacia in premature infants: a threat until term.

The purposes of this study are (1) to describe a "late-onset" form of cystic periventricular leukomalacia eventually appearing in premature infants whose neurological assessments were normal in the first month of life; (2) to retrospectively evaluate its incidence among a large population of premature infants; (3) to suggest that a few unexpected complications of prematurity may trigger the development of white matter damage, even several weeks after birth. Retrospective study in a population of 1452 surviving infants after 5 days born before 33 weeks. We identified 10 cases of late-onset cystic periventricular leukomalacia appearing beyond the first 5 weeks of life. In 8 cases, an intercurrent event associated with a systemic inflammatory response preceded the appearance of cysts: necrotizing enterocolitis (n = 5), septicemia (n = 2 cases), strangulated inguinal hernia in one infant. Neurological surveillance should be repeated until discharge in very preterm infants, especially after the occurrence of an intercurrent complication coming along with a systemic inflammatory response.

Development and initial validation of the EDIN scale, a new tool for assessing prolonged pain in preterm infants.

OBJECTIVE: To develop and validate a scale suitable for use in clinical practice as a tool for assessing prolonged pain in premature infants. METHODS: Pain indicators identified by observation of preterm infants and selected by a panel of experts were used to develop the EDIN scale (Echelle Douleur Inconfort Nouveau-Né, neonatal pain and discomfort scale). A cohort of preterm infants was studied prospectively to determine construct validity, inter-rater reliability, and internal consistency of the scale. RESULTS: The EDIN scale uses five behavioural indicators of prolonged pain: facial activity, body movements, quality of sleep, quality of contact with nurses, and consolability. The validation study included 76 preterm infants with a mean gestational age of 31.5 weeks. Inter-rater reliability was acceptable, with a kappa coefficient range of 0.59-0.74. Internal consistency was high: Cronbach's alpha coefficients calculated after deleting each item ranged from 0.86 to 0.94. To establish construct validity, EDIN scores in two extreme situations (pain and no pain) were compared, and a significant difference was observed. CONCLUSIONS: The validation data suggest that the EDIN is appropriate for assessing prolonged pain in preterm infants. Further studies are warranted to obtain further evidence of construct validity by comparing scores in less extreme situations.

[Pediatric follow-up network in the south Ile-de-France]. / Le réseau de suivi pédiatrique du sud de l'Ile-de-France.

Regional organization of perinatal care, with maternal tranfers, has largely contributed to the increasing survival rate of very preterm infants. Nevertheless, follow-up and care the of these surviving children at risk of neurodevelopmental impairment are insufficiently organized. For this reason, a pediatric network of care and follow-up has been set up in continuity of a regional perinatal network ("réseau périnatal et réseau pédiatrique du sud-ouest de l'Ile de France"). Two missions are devoted to this network: organize local follow-up and care of infants at risk of abnormal outcome and collect follow-up data with specific forms. One form per year of age is to be filled with Items concerning growth, health, cognitive and motor development, family and society integration, quality of life.

[Anoxic encephalopathy of the term neonate and brain hypothermia]. / Encéphalopathie anoxique du nouveau-né à terme et hypothermie cérébrale.

The outcome of term newborns with birth asphyxia and moderate to severe hypoxic ischemic encephalopathy remains very poor. After the primary phase of energy failure during asphyxia, neuronal cell metabolism may deteriorate in a secondary phase of brain injury. The window between these two phases opens the way to potential neuroprotective treatments such as brain cooling. Promising experimental data on controlled hypothermia need to be examined with clinical trials.

Methylprednisolone, an alternative to dexamethasone in very premature infants at risk of chronic lung disease.

OBJECTIVE: To evaluate the benefits and the medium-term side effects of methylprednisolone in very preterm infants at risk of chronic lung disease. STUDY DESIGN: Forty-five consecutive preterm infants (< 30 weeks' gestation) at risk of chronic lung disease were treated at a mean postnatal age of 16 days with a tapering course of methylprednisolone. The outcome of treatment was assessed by comparison with 45 consecutive historical cases of infants treated with dexamethasone; the infants did not differ in baseline characteristics. RESULTS: There were no differences between groups in the rate of survivors without chronic lung disease. Infants treated with methylprednisolone had a higher rate of body weight gain during the treatment period (median 120 g, range 0 to 190, vs. 70 g, range -110 to 210, P = 0.01) and between birth and the age of 40 weeks (median 1660 g, range 1170-2520, vs. 1580 g, range 1,040 to 2,120, P = 0.02). The incidence of both glucose intolerance requiring insulin (0 % vs. 18 %, P = 0.006) and cystic periventricular leukomalacia (2 % vs. 18%, P = 0.03) was lower among methylprednisolone-treated infants. CONCLUSION: Our observations confirm methylprednisolone to be as effective as dexamethasone and to have fewer side effects. A randomized control trial is needed to further study the efficacy and safety of methylprednisolone in very premature infants at risk of chronic lung disease.

Severe congenital dyserythropoietic anaemia type I: prenatal management, transfusion support and alpha-interferon therapy.

We report a case of congenital dyserythropoietic anaemia, type I, with severe pre- and postnatal manifestations. Exchange transfusions were required for fetal anaemia (3.5 g/dl) at 28 and 30 weeks of gestation. Transfusions were administered at birth (Caesarean section at week 35) and at regular intervals thereafter. At 14 months, alpha-interferon therapy was initiated (106 units three times a week). This resulted in stabilization of the haemoglobin at or above 11 g/dl and a reduction in the percentage of erythroblasts with ultrastructurally abnormal heterochromatin. After 9 months, the dose of alpha-interferon was decreased to 106 units twice a week. No relapse of anaemia was noted during an additional 4 months of follow-up.

The relationships between antenatal management, the cause of delivery and neonatal outcome in a large cohort of very preterm singleton infants.

OBJECTIVE: To determine whether the cause of very preterm delivery influences neonatal outcome. DESIGN: A cohort study of 685 consecutive singletons born before 33 weeks of gestation. METHODS: Causes of birth and perinatal outcome variables were correlated for statistical significance by uni- and multi-variate analyses. RESULTS: Intrauterine growth retardation or pre-eclampsia were associated with a higher rate of respiratory distress syndrome compared with prolonged rupture of membranes, after controlling for gestational age, antenatal corticosteroid therapy, antenatal antibiotic administration, mode of delivery and origin (inborn or outborn) (adjusted OR 3.12; 95% CI 1.55-6.28). The prevalence of grade 3-4 intraventricular haemorrhage or cystic periventricular leukomalacia was 25% in newborn babies born after intrauterine infection or prolonged rupture of membranes. Among infants born after intrauterine growth retardation/pre-eclampsia, the rate of severe intraventricular haemorrhage was 3.2% and the rate of periventricular leukomalacia was 0.9%. Compared with intrauterine infection and after controlling for potential confounding covariates, intrauterine growth retardation/pre-eclampsia was associated with a lower rate of periventricular leukomalacia (adjusted OR 0.08; 95% CI 0.02-0.41). In the same multiple logistic regression model, antenatal corticosteroid administration was associated with a lower incidence of periventricular leukomalacia (adjusted OR 0.36; 95% CI 0.16-0.79). CONCLUSIONS: The cause of very preterm delivery has an important influence on neonatal outcome.

Outcome of premature infants delivered after prolonged premature rupture of membranes before 25 weeks of gestation.

OBJECTIVE: To identify factors influencing the outcome of premature infants delivered after prolonged premature rupture of membranes before 25 weeks' gestation. DESIGN AND POPULATION: All premature infants with gestational age <34 weeks, either inborn or outborn, with history of rupture of membranes before 25 weeks' gestation, admitted to our NICU between January 1992 and July 1997, were eligible for this retrospective study. Collected information included birth weight, gestational age at rupture of membranes and at delivery, duration between rupture of membranes and delivery (latency period), severity of oligohydramnios, pre- and post-natal managements, and follow-up of survivors. RESULTS: A total of 28 neonates fulfilled the inclusion criteria. Despite new strategies of ventilation and optimal management, the overall mortality rate was 43% (12/28). Nonsurvivors were significantly less mature at rupture of membranes, and had severe oligohydramnios (anamnios). We also noted less antenatal corticosteroids and antibiotic therapy in this group. Nine of eleven infants (82%) following rupture of membranes before 22 weeks' gestation died shortly after birth. The two remaining infants developed severe bronchopulmonary dysplasia. Nine deaths occurred in thirteen cases (69%) of anamnios. The major death causes were refractory respiratory failure and neurologic complications. Half of all survivors (8/16) developed bronchopulmonary dysplasia. CONCLUSION: The outcome of premature infants following prolonged premature rupture of membranes before 25 weeks' gestation is influenced by gestational age at rupture, severity of oligohydramnios, and antenatal antibiotics and corticosteroids. Neonates with rupture of membranes before 22 weeks have a very low chance of survival at the present time.

Prenatal blockade of vasoactive intestinal peptide alters cell death and synaptic equipment in the murine neocortex.

Vasoactive intestinal peptide (VIP) is a potent growth factor that stimulates murine neocortical astrocyte genesis during the period of ontogenesis corresponding to premature delivery in humans. In rodents, part of the VIP supplied to the fetal brain is maternal VIP that crosses the placenta. If these data also apply to human brain development, premature newborns may be partly VIP-deficient because of loss of the maternal supply, and this may adversely affect their brain development. The goal of the present study was to determine the effects of VIP blockade during mouse neocortical astrocyte genesis on neuritic survival and maturation. VIP blockade by a specific VIP antagonist on embryonic d 17 and 18 induced transient, postnatal depletion of astrocytes in the upper neocortical layers. Combined use of in situ DNA fragmentation analysis (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling method, a marker of cell death); immunohistochemical detection of synaptophysin, microtubule-associated proteins, and neurofilaments; and quantification of mRNA for synaptophysin and N-methyl-D-aspartate R1 receptor subunit revealed that early VIP blockade significantly altered programmed neuritic death and impaired neuritic differentiation. VIP inhibition induced 1) exaggerated postnatal terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling of cortical neurons, 2) long-term overexpression of synaptophysin and N-methyl-D-aspartate R1 receptor subunit, and 3) long-term overexpression of microtubule-associated protein-5 and neurofilament 160 kD. Although the functional consequences of this deviant pattern of murine neocortical development remain to be determined, these data open up new avenues for investigating some of the cognitive deficits observed in human premature infants.

Amniotic fluid concentrations of interleukin-1beta, interleukin-6 and TNF-alpha in chorioamnionitis before 32 weeks of gestation: histological associations and neonatal outcome.

OBJECTIVES: To test the association between cytokine levels in the amniotic fluid and (i) the vascular invasion phase of intrauterine infection, (ii) the occurrence of periventricular leukomalacia; to assess the correlation between C-reactive protein levels, a recognised biological marker of inflammation in maternal serum and cytokine levels in the amniotic fluid. DESIGN: Prospective clinical study. SETTING: Fetal medicine unit and neonatal intensive care unit, Antoine Beclere Hospital, Clamart, France. SAMPLE: Thirty-one pregnancies complicated by chorioamnionitis leading to birth before 32 weeks of gestation. METHODS: Interleukin 1-beta, Interleukin 6 and TNF-alpha prospectively measured in the amniotic fluid. Histological examination of the placenta. Ultrasound examination and magnetic resonance imaging of the brains of the newborn infants performed within the first week of life. MAIN OUTCOME MEASURES: The occurrence of periventricular leukomalacia was assessed by transfontanellar ultrasound and magnetic resonance imaging. RESULTS: There was a significant positive correlation between the occurrence of histological chorioamnionitis, vascular extension of infection of the membranes, maternal inflammatory syndrome and neonatal sepsis. A strong association was found between maternal serum C-reactive protein concentrations and cytokine levels in the amniotic fluid. Interleukin-1beta was the best predictor of vascular extension of chorioamnionitis, and TNF-alpha was the best predictor of the development of severe early neonatal infection. There was no association between the amniotic fluid levels of cytokines and the development of periventricular leukomalacia. CONCLUSIONS: These data suggest that IL-1beta, IL-6 and TNF-alpha are produced in relation to intrauterine inflammation and infection, but cannot be directly implicated in the development of fetal cerebral white matter lesions.

Inhaled salbutamol and beclomethasone for preventing broncho-pulmonary dysplasia: a randomised double-blind study.

UNLABELLED: Early inflammatory lesions and bronchial hyperresponsiveness are characteristics of the respiratory distress in premature neonates and are susceptible to aggravation by assisted ventilation. We hypothesized that treatment with inhaled salbutamol and beclomethasone might be of clinical value in the prevention of bronchopulmonary dysplasia (BPD) in ventilator-dependent premature neonates. The study was double-blinded and placebo controlled. We studied 173 infants of less than 31 weeks of gestational age, who needed ventilatory support at the 10th postnatal day. They were randomised to four groups and received either placebo + placebo, placebo + salbutamol, placebo + beclomethasone or beclomethasone + salbutomol, respectively for 28 days. The major criteria for efficacy were: diagnosis of BPD (with score of severity), mortality, duration of ventilatory support and oxygen therapy. The trial groups were similar with respect to age at entry (9.8-10.1 days), gestational age (27.6-27.8 weeks), birth weight and oxygen dependence. We did not observe any significant effect of treatment on survival, diagnosis and severity of BPD, duration of ventilatory support or oxygen therapy. For instance, the odds-ratio (95% confidence interval) for severe or moderate BPD were 1.04 (0.52-2.06) for inhaled beclomethasone and 1.54 (0.78-3.05) for inhaled salbutamol. CONCLUSION: This randomised prospective trial does not support the use of treatment with inhaled beclomethasone, salbutamol or their combination in the prevention of BPD in premature ventilated neonates.

[Periventricular leukomalacia. I. Histological and pathophysiological aspects]. / Les leucomalacies périventriculaires. I. Aspects histologiques et étiopathogéniques.

The term 'periventricular leukomalacia' (PVL) usually covers necrotic and/or gliotic lesions from perinatal origin occurring in the periventricular ring of telencephalic white matter. PVLs are found post-mortem in one third of brains from autopsies of premature infants; PVLs are diagnosed in 4 to 10% of infants born before 33 weeks of gestation and remaining alive more than 3 days after birth. PVL is very rare in at term infants. The proportion of PVLs from prenatal origin is estimated between one third and one half of cases. Recent progresses in neuroepidemiology, developmental neurobiology and imaging methods permit to revisit the pathophysiology of PVLs on a multifactorial basis. The final result of these multiple factors seem to be calcium influx due to glutamatergic overactivation triggered by cytokines, infection and inflammation, and deficit in neurotrophic factors. Periventricular topography can be explained by properties of intracerebral vascular wall at this stage of angiogenesis and by perfusion failure/hypoxia.