Thierry Lacaze-Masmonteil

PERIVENTRICULAR LEUKOMALACIA: RISK FACTORS REVISITED

The dramatic improvement in neonatal care during the last decade did not succeed in reducing the incidence of periventricular leukomalacia (PVL), suggesting that prenatal events may be the main target for PVL prevention. The studied cohort included 753 very preterm infants born between 24 and 32 weeks of gestational age, admitted to the intensive care unit and surviving at least 7 days; 69 (9.2%) of these infants had a diagnosis of cystic PVL. The highest PVL frequency was observed among the infants bom at 28 weeks of gestation (16%). Inflammatory prenatal events occurring during the last days or weeks before delivery and PVL occurrence are strongly correlated. Indeed, the combination of intra‐uterine infection and premature rupture of membranes is associated with a very high risk (22%). Prolongation of pregnancy with tocolysis for more than 24 hours also carries a significant. 8% risk of PVL. In contrast, chronic fetal distress of long duration, such as severe intra‐uterine growth retardation and pre‐cclampsia, is seldom followed by PVL (<2% risk). Similarly, rapid unexpected deliveries entail a minimal PVL risk (4%). Experimental and epidemiological confirmations of these data would have an influence on the management of both the preterm onset of labour and the premature rupture of membranes.

A Multicenter, Randomized, Controlled Trial of Lucinactant Versus Poractant Alfa Among Very Premature Infants at High Risk for Respiratory Distress Syndrome

Background. Available therapeutic surfactants are either animal-derived or non–protein-containing synthetic products. Animal-derived surfactants contain variable amounts of surfactant apoproteins, whereas the older-generation synthetic products contain only phospholipids and lack surfactant proteins (SPs). Both decrease morbidity and mortality rates associated with respiratory distress syndrome (RDS) among preterm infants, compared with placebo. However, excess mortality rates have been observed with non–protein-containing synthetic surfactants, compared with the animal-derived products. Evidence suggests that synthetic surfactants consisting solely of phospholipids can be improved with the addition of peptides that are functional analogs of SPs. Lucinactant is a new synthetic peptide-containing surfactant that contains sinapultide, a novel, 21-amino acid peptide (leucine and lysine repeating units, KL4 peptide) designed to mimic human SP-B. It is completely devoid of animal-derived components. Objective. We hypothesized that the outcomes for premature infants treated with lucinactant and poractant alfa would be similar. Therefore, we compared lucinactant (Surfaxin; Discovery Laboratories, Doylestown, PA) with porcine-derived, poractant alfa (Curosurf; Chiesi Farmaceutici, Parma, Italy) in a trial to test for noninferiority. Methods. A total of 252 infants born between 24 and 28 weeks of completed gestation, with birth weights between 600 and 1250 g, were assigned randomly in a multicenter, multinational, noninferiority, randomized, controlled study to receive either lucinactant (n = 124) or poractant alfa (n = 128) within 30 minutes of life. The primary outcome was the incidence of being alive without bronchopulmonary dysplasia (BPD) through 28 days of age. Key secondary outcomes included death at day 28 and 36 weeks postmenstrual age (PMA), air leaks, neuroimaging abnormalities, and other complications related to either prematurity or RDS. An independent, international, data and safety monitoring committee monitored the trial. Results. The treatment difference between lucinactant and poractant alfa for survival without BPD through 28 days was 4.75% (95% confidence interval [CI]: −7.3% to 16.8%) in favor of lucinactant, with the lower boundary of the 95% CI for the difference, ie, −7.3%, being greater than the prespecified noninferiority margin of −14.5%. At 28 days, 45 of 119 infants given lucinactant were alive without BPD (37.8%; 95% CI: 29.1–46.5%), compared with 41 of 124 given poractant alfa (33.1%; 95% CI: 24.8–41.3%); at 36 weeks PMA, the rates were 64.7% and 66.9%, respectively. The corresponding mortality rate through day 28 for the lucinactant group was lower than that for the poractant alfa group (11.8% [95% CI: 6.0–17.6%] vs 16.1% [95% CI: 9.7–22.6%]), as was the rate at 36 weeks PMA (16% and 18.5%, respectively). There were no differences in major dosing complications. In addition, no significant differences were observed in the incidences of common complications of prematurity, including intraventricular hemorrhage (grades 3 and 4) and cystic periventricular leukomalacia (lucinactant: 14.3%; poractant alfa: 16.9%). Conclusions. Lucinactant and poractant alfa were similar in terms of efficacy and safety when used for the prevention and treatment of RDS among preterm infants. The ability to enhance the performance of a synthetic surfactant with the addition of a peptide that mimics the action of SP-B, such as sinapultide, brings potential advantages to exogenous surfactant therapy.

Amniotic fluid concentrations of Interleukin‐1β, Interleukin‐6 and TNF‐α 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.

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.

A novel mouse model of Ureaplasma-induced perinatal inflammation: effects on lung and brain injury

Chorioamnionitis is associated with increased lung and brain injury in premature infants. Ureaplasma is the microorganisms most frequently associated with preterm birth. Whether Ureaplasma-induced antenatal inflammation worsens lung and brain injury is unknown. We developed a mouse model combining antenatal Ureaplasma infection and postnatal oxygen exposure. Intraamniotic Ureaplasma Parvum (UP) increased proinflammatory cytokines in placenta and fetal lungs. Antenatal exposure to UP or broth caused mild postnatal inflammation and worsened oxygen-induced lung injury. Antenatal UP exposure induced central microgliosis and disrupted brain development as detected by decreased number of calbindin-positive and calretinin-positive neurons in the neocortex. Postnatal oxygen decreased calretinin-positive neurons in the neocortex but combined with antenatal UP exposure did not worsen brain injury. Antenatal inflammation exacerbates the deleterious effects of oxygen on lung development, but the broth effects prohibit concluding that UP by itself is a compounding risk factor for bronchopulmonary dysplasia. In contrast, antenatal UP-induced inflammation alone is sufficient to disturb brain development. This model may be helpful in exploring the pathophysiology of perinatal lung and brain injury to develop new protective strategies.

Are neonatal brain lesions due to intrauterine infection related to mode of delivery

Studies of antenatal and intrapartum factors involved in the development of cerebral palsy have identified intrauterine infection and chorioamnionitis as high risk situations for white matter damage, especially periventricular ledcomalacia. To characterise adverse or protective perinatal factors further, we undertook a multiple regression analysis of selected perinatal events in a population of 110 inborn premature neonates with documented chorioamnionitis. In the total population of 110 infants delivered at between 25 and 32 weeks, 101 (92%) survived the first week of life and two were subsequently excluded. Of the 99 remaining infants, 20 (20%) developed periventricular leukomalacia including 16 (80%) cystic lesions. Forty‐five (45%) babies were born by lower segment caesarean section, and for 37 of these, this was carried out before labour. Fetal presentation at delivery was breech in 14 (26%) of those born vaginally and 23 (52%) of those born by lower segment caesarean section (OR 3 [95% CI 1.–71). Among predetermined perinatal risk factors for periventricular leukomalacia, logistic regression analysis showed that delivery by caesarean section was associated with a dramatic decrease in the incidence of periventricular leukomalacia (OR 0.5 [95% CI 0.4–0.71). These preliminary results warrant confirmation and preferably a prospective study before considering caesarean section as a protective perinatal factor of periventricular leukomalacia.

Neonatal and Neurodevelopmental Outcomes of Very Low Birth Weight Infants with Histologic Chorioamnionitis

OBJECTIVE To determine survival and neurodevelopmental outcomes at 18 months corrected age among very low birth weight infants ≤ 32 weeks gestation with histologic chorioamnionitis. STUDY DESIGN Observational, regionalized, single-center cohort study with prospective follow-up. RESULTS Of the 628 infants meeting the selection criteria, 303 (48%) were born to mothers with evidence of histologic chorioamnonitis. Neonates with histologic chorioamnonitis were of lower gestational age and birth weight. On univariate analysis, they were more likely to have hypotension, bronchopulmonary dysplasia, severe intraventricular hemorrhage, severe retinopathy of prematurity, early-onset sepsis, and death. Infants with histologic chorioamnonitis were more likely to have any neurodevelopmental impairment, specifically, mental delay with a lower mental developmental index. When adjusting for perinatal variables, histologic chorioamnonitis had a protective effect on mortality rates (adjusted OR = 0.44, 95% CI: 0.24-0.8; P = .01; n = 619), had a nonsignificant effect on neurodevelopmental impairment (adjusted odds ratio = 1.33, 95% CI: 0.82-2.17; P = .25; n = 496), and was associated with a 4-point lower mental developmental index at 18-months follow-up (adjusted difference -3.93, 95% CI: -7.52 to -0.33; P = .03; n = 496). CONCLUSIONS Although infants with histologic chorioamnonitis were at an increased risk for death and neurodevelopmental impairment, after multivariate analyses, histologic chorioamnonitis was not associated with adverse long-term outcomes. Results suggest fetal protection from treatment-responsive maternal infection and inflammation.

Chest computed tomography findings in bronchopulmonary dysplasia and correlation with lung function

Objective: With changes in the predominant pathogenic factors in the new form of bronchopulmonary dysplasia (BPD), a different pattern of CT findings may be expected. This study aimed to (1) describe CT findings in infants with BPD and (2) correlate the CT findings with lung function abnormalities. Study design and method: Retrospective review of 41 very low birthweight infants with BPD, who were referred for pulmonary investigations at between 10 and 20 months after birth because of persistent respiratory symptoms, and underwent CT and lung function tests. Results: None of the infants had normal CT findings. The most frequent abnormalities were hyperlucent areas (n = 36; 88%), linear opacities (n = 39; 95%), and triangular subpleural opacities (n = 26; 63%). Bronchiectasis was not seen. None of the CT abnormalities correlated with the maximum expiratory flow at functional residual capacity (VmaxFRC). In contrast, increased number of subpleural opacities and limited linear opacities were associated with low FRC and longer duration of neonatal oxygen exposure. The numbers of triangular subpleural opacities also correlated with duration of mechanical ventilation. Conclusions: Despite advances in neonatal care, many CT findings in infants with BPD are similar to those observed in the pre-surfactant era, and are still associated with duration of supplemental oxygen and mechanical ventilation. The absence of bronchial involvement in the present study was the most striking difference from previous studies.

A systematic review of intentional delivery in women with preterm prelabor rupture of membranes

Objective. To evaluate the effect of intentional delivery versus expectant management in women with preterm prelabor rupture of membranes (PPROM). Methods. We searched electronic databases and trials registries, contacted experts, and checked reference lists of relevant studies. Studies were included if they were randomized controlled trials comparing intentional delivery versus expectant management after PPROM, the gestational age of participants was between 30 and 36 weeks, and the study reported one of several pre-determined outcomes. Results. Four studies were included in the meta-analysis. No difference was found between intentional delivery and expectant management in neonatal intensive care unit (NICU) length of stay (LOS) (weighted mean difference (WMD) −0.81 day, 95% confidence interval (CI) −1.66, 0.04), respiratory distress syndrome (risk difference (RD) −0.01, 95% CI −0.07, 0.06), and confirmed neonatal sepsis (RD −0.01, 95% CI −0.05, 0.04). One study found a significantly lower incidence of suspected neonatal sepsis among the intentional delivery group (RD −0.31, 95% CI −0.50, −0.12; number needed to treat (NNT) 3, 95% CI 2, 8). Maternal LOS was significantly shorter for the intentional delivery group (WMD −1.39 day, 95% CI −2.03, −0.75). There was a significant difference in the incidence of clinical chorioamnionitis favoring intentional delivery (RD −0.16, 95% CI −0.23, −0.10; NNT 6, 95% CI 5, 11). There was no significant difference in the incidence of other maternal outcomes, including cesarean section (RD 0.05, 95% CI −0.01, 0.11). Conclusions. Intentional delivery may be favorable to expectant management for some maternal outcomes (chorioamnionitis and LOS). There is insufficient evidence to suggest that either strategy is beneficial or harmful for the baby. Large multicenter trials with primary neonatal outcomes are required to assess whether intentional delivery is associated with less neonatal morbidity.

Functional genetic variation in NFKBIA and susceptibility to childhood asthma, bronchiolitis, and bronchopulmonary dysplasia.

Respiratory diseases are the most frequent chronic illnesses in babies and children. Although a vigorous innate immune system is critical for maintaining lung health, a balanced response is essential to minimize damaging inflammation. We investigated the functional and clinical impact of human genetic variants in the promoter of NFKBIA, which encodes IκBα, the major negative regulator of NF-κB. In this study, we quantified the functional impact of NFKBIA promoter polymorphisms (rs3138053, rs2233406, and rs2233409) on promoter-driven protein expression, allele-specific and total NFKBIA mRNA expression, IκBα protein expression, and TLR responsiveness; mapped innate immune regulatory networks active during respiratory syncytial virus infection, asthma, and bronchopulmonary dysplasia; and genotyped and analyzed independent cohorts of children with respiratory syncytial virus infection, asthma, and bronchopulmonary dysplasia. Genetic variants in the promoter of NFKBIA influenced NFKBIA gene expression, IκBα protein expression, and TLR-mediated inflammatory responses. Using a systems biology approach, we demonstrated that NFKBIA/IκBα is a central hub in transcriptional responses of prevalent childhood lung diseases, including respiratory syncytial virus infection, asthma, and bronchopulmonary dysplasia. Finally, by examining independent pediatric lung disease cohorts, we established that this immunologically relevant genetic variation in the promoter of NFKBIA is associated with differential susceptibility to severe bronchiolitis following infection with respiratory syncytial virus, airway hyperresponsiveness, and severe bronchopulmonary dysplasia. These data highlight the importance of negative innate immune regulators, such as NFKBIA, in pediatric lung disease and begin to unravel common aspects in the genetic predisposition to bronchopulmonary dysplasia, bronchiolitis, and childhood asthma.