Nouvelles approches dans la prise en charge de l'infection congénitale à cytomégalovirus : du dépistage au traitement

Congenital cytomegalovirus (CMV) infection is the most common congenital infection and the leading cause of infectious neurosensory disability in newborns. Thus, we wished to improve the available therapeutic arsenal and to organize the management of women from the beginning of pregnancy allowing access to antenatal treatment. Our work had two complementary objectives: 1) to set up and evaluate the interest of a systematic screening of CMV infection during pregnancy in our type 3 maternity hospital, at the CHRU of Limoges. Our results confirmed our advice on the interest of screening for CMV infection during pregnancy according, nevertheless, to modalities different from those currently implemented in our center. 2) Evaluation of the inhibitory potential of anti-CMV antibodies and new anti-virals, alone or in combination, in cell cultures and from ex vivo models of placental explant cultures. Our trials have shown the efficacy of hyperimmune immunoglobulins in preventing infection transmission, especially when administered weekly. Nevertheless, this management strategy will only be valid if a systematic monthly screening is implemented during the first trimester of pregnancy, the fetal period most at risk of severe sequelae. The range of anti-CMV antivirals is wide and we have shown the interest of combining molecules targeting different mechanisms of the viral cycle to optimize their efficacy without increasing their toxicity, as these molecules alone do not seem to allow a total inhibition of the virus.L’infection congénitale à cytomégalovirus (CMV) est la plus fréquente des infections congénitales et la première cause de handicap neurosensoriel d’origine infectieuse chez les nouveau-nés. Ainsi, nous avons souhaité améliorer l’arsenal thérapeutique disponible et organiser la prise en charge des femmes dès le début de la grossesse permettant l’accès au traitement anténatal. Nos travaux ont visé deux objectifs complémentaires 1) la mise en place et l’évaluation de l’intérêt d’un dépistage systématisé de l’infection à CMV durant la grossesse au sein de notre maternité de type 3, au CHRU de Limoges. Nos résultats nous ont confortée dans notre position sur l’intérêt du dépistage de l’infection à CMV durant la grossesse selon, néanmoins, des modalités différentes de celles actuellement mises en place dans notre centre. 2) l’évaluation du potentiel inhibiteur d’anticorps anti-CMV et de nouveaux anti-viraux seuls ou en association, en cultures cellulaires et à partir de modèles ex vivo de cultures d’explants placentaires. Nos essais ont montré l’efficacité des Immunoglobulines hyperimmunes dans la prévention de la transmission de l’infection, en particulier lorsque celles-ci étaient administrées de façon hebdomadaire. Néanmoins cette stratégie de prise en charge ne pourra être valide que par la mise en place d’un dépistage systématisé mensuel au cours du 1er trimestre de grossesse, période fœtale la plus à risque de séquelles sévères. L’éventail des molécules antivirales anti-CMV est large et nous avons montré l’intérêt de combiner des molécules ciblant différents mécanismes du cycle viral pour optimiser leur efficacité sans augmenter leur toxicité, ces molécules ne semblant pas à elles seules permettre une inhibition totale du virus

New approaches to the management of congenital cytomegalovirus infection : from screening to treatment

L’infection congénitale à cytomégalovirus (CMV) est la plus fréquente des infections congénitales et la première cause de handicap neurosensoriel d’origine infectieuse chez les nouveau-nés. Ainsi, nous avons souhaité améliorer l’arsenal thérapeutique disponible et organiser la prise en charge des femmes dès le début de la grossesse permettant l’accès au traitement anténatal. Nos travaux ont visé deux objectifs complémentaires 1) la mise en place et l’évaluation de l’intérêt d’un dépistage systématisé de l’infection à CMV durant la grossesse au sein de notre maternité de type 3, au CHRU de Limoges. Nos résultats nous ont confortée dans notre position sur l’intérêt du dépistage de l’infection à CMV durant la grossesse selon, néanmoins, des modalités différentes de celles actuellement mises en place dans notre centre. 2) l’évaluation du potentiel inhibiteur d’anticorps anti-CMV et de nouveaux anti-viraux seuls ou en association, en cultures cellulaires et à partir de modèles ex vivo de cultures d’explants placentaires. Nos essais ont montré l’efficacité des Immunoglobulines hyperimmunes dans la prévention de la transmission de l’infection, en particulier lorsque celles-ci étaient administrées de façon hebdomadaire. Néanmoins cette stratégie de prise en charge ne pourra être valide que par la mise en place d’un dépistage systématisé mensuel au cours du 1er trimestre de grossesse, période fœtale la plus à risque de séquelles sévères. L’éventail des molécules antivirales anti-CMV est large et nous avons montré l’intérêt de combiner des molécules ciblant différents mécanismes du cycle viral pour optimiser leur efficacité sans augmenter leur toxicité, ces molécules ne semblant pas à elles seules permettre une inhibition totale du virus.Congenital cytomegalovirus (CMV) infection is the most common congenital infection and the leading cause of infectious neurosensory disability in newborns. Thus, we wished to improve the available therapeutic arsenal and to organize the management of women from the beginning of pregnancy allowing access to antenatal treatment. Our work had two complementary objectives: 1) to set up and evaluate the interest of a systematic screening of CMV infection during pregnancy in our type 3 maternity hospital, at the CHRU of Limoges. Our results confirmed our advice on the interest of screening for CMV infection during pregnancy according, nevertheless, to modalities different from those currently implemented in our center. 2) Evaluation of the inhibitory potential of anti-CMV antibodies and new anti-virals, alone or in combination, in cell cultures and from ex vivo models of placental explant cultures. Our trials have shown the efficacy of hyperimmune immunoglobulins in preventing infection transmission, especially when administered weekly. Nevertheless, this management strategy will only be valid if a systematic monthly screening is implemented during the first trimester of pregnancy, the fetal period most at risk of severe sequelae. The range of anti-CMV antivirals is wide and we have shown the interest of combining molecules targeting different mechanisms of the viral cycle to optimize their efficacy without increasing their toxicity, as these molecules alone do not seem to allow a total inhibition of the virus

Potential of Anti-CMV Immunoglobulin Cytotect CP® In Vitro and Ex Vivo in a First-Trimester Placenta Model

Background: Congenital CMV infection is the leading cause of neonatal neurological deficit. We herein studied in vitro and ex vivo the potential of the hyperimmune globulin Cytotect CP® (Biotest, Germany) for congenital infection prevention and treatment. Methods: In vitro neutralization assays were conducted in fibroblasts and retinal epithelial cells on the CMV strains TB40/E and VHL/E to determine the 50% and 90% neutralizing doses (ND50 and ND90). The toxicity was assessed by measuring LDH release. Ex vivo assays were conducted in first-trimester villi explants with the TB40/E strain, namely, neutralization assays, the prevention of villi infection, and the inhibition of viral replication in infected villi. Viability was assessed by β-HCG quantification in supernatants. Results: The in vitro neutralization tests showed that Cytotect CP®® inhibits the development of infection foci (DN50: 0.011–0.014 U/mL for VHL/E and 0.032–0.033 U/mL for TB40E) without any toxicity. In the ex vivo neutralization assays, the DN50 were 0.011 U/mL on day 7 and 0.093 U/mL on day 14. For the prevention of villi infection, the EC50 was 0.024 U/mL on day 7. Cytotect-CP® did not inhibit viral growth in infected villi. No impact on villi viability was observed. Conclusions: These results sustained that Cytotect CP® has the potential to prevent CMV congenital infection

Potential of Anti-CMV Immunoglobulin Cytotect CP^® In Vitro and Ex Vivo in a First-Trimester Placenta Model

Background: Congenital CMV infection is the leading cause of neonatal neurological deficit. We herein studied in vitro and ex vivo the potential of the hyperimmune globulin Cytotect CP® (Biotest, Germany) for congenital infection prevention and treatment. Methods: In vitro neutralization assays were conducted in fibroblasts and retinal epithelial cells on the CMV strains TB40/E and VHL/E to determine the 50% and 90% neutralizing doses (ND50 and ND90). The toxicity was assessed by measuring LDH release. Ex vivo assays were conducted in first-trimester villi explants with the TB40/E strain, namely, neutralization assays, the prevention of villi infection, and the inhibition of viral replication in infected villi. Viability was assessed by β-HCG quantification in supernatants. Results: The in vitro neutralization tests showed that Cytotect CP®® inhibits the development of infection foci (DN50: 0.011–0.014 U/mL for VHL/E and 0.032–0.033 U/mL for TB40E) without any toxicity. In the ex vivo neutralization assays, the DN50 were 0.011 U/mL on day 7 and 0.093 U/mL on day 14. For the prevention of villi infection, the EC50 was 0.024 U/mL on day 7. Cytotect-CP® did not inhibit viral growth in infected villi. No impact on villi viability was observed. Conclusions: These results sustained that Cytotect CP® has the potential to prevent CMV congenital infection

Machine learning analysis of pregnancy data enables early identification of a subpopulation of newborns with ASD

International audienceTo identify newborns at risk of developing ASD and to detect ASD biomarkers early after birth, we compared retrospectively ultrasound and biological measurements of babies diagnosed later with ASD or neurotypical (NT) that are collected routinely during pregnancy and birth. We used a supervised machine learning algorithm with a cross-validation technique to classify NT and ASD babies and performed various statistical tests. With a minimization of the false positive rate, 96% of NT and 41% of ASD babies were identified with a positive predictive value of 77%. We identified the following biomarkers related to ASD: sex, maternal familial history of auto-immune diseases, maternal immunization to CMV, IgG CMV level, timing of fetal rotation on head, femur length in the 3rd trimester, white blood cell count in the 3rd trimester, fetal heart rate during labor, newborn feeding and temperature difference between birth and one day after. Furthermore, statistical models revealed that a subpopulation of 38% of babies at risk of ASD had significantly larger fetal head circumference than age-matched NT ones, suggesting an in utero origin of the reported bigger brains of toddlers with ASD. Our results suggest that pregnancy follow-up measurements might provide an early prognosis of ASD enabling pre-symptomatic behavioral interventions to attenuate efficiently ASD developmental sequels

Is laterality of congenital diaphragmatic hernia a reliable prognostic factor? French national cohort study

International audienceObjectives: The objective of this study was to assess whether the laterality of congenital diaphragmatic hernia (CDH) was a prognostic factor for neonatal survival.Methods : This was a cohort study using the French national database of the Reference Center for Diaphragmatic Hernias. The principal endpoint was survival after hospitalization in intensive care.We made a comparative study between right CDH and left CDH by univariate and multivariate analysis. Terminations and stillbirths were excluded from analyses of neonatal outcomes.Results: A total of 506 CDH were included with 67 (13%) right CDH and 439 left CDH (87%). Rate of survival was 49% for right CDH and 74% for left CDH (P < .01). Multivariate analysis showed two factors significantly associated with mortality: thoracic herniation of liver (OR 2.27; IC 95% [1.07-4.76]; P = .03) and lung-to-head-ratio over under expected (OR 2.99; IC 95% [1.41-6.36]; P < .01). Side of CDH was not significantly associated with mortality (OR 1.87; IC 95% [0.61-5.51], P = .26).Conclusion : Rate of right CDH mortality is more important than left CDH. Nevertheless after adjusting for lung-to-head-ratio and thoracic herniation of liver, right CDH does not have a higher risk of mortality than left CDH

Neonatal outcomes for women at risk of preterm delivery given half dose versus full dose of antenatal betamethasone: a randomised, multicentre, double-blind, placebo-controlled, non-inferiority trial

International audienceBackgroundAntenatal betamethasone is recommended before preterm delivery to accelerate fetal lung maturation. However, reports of growth and neurodevelopmental dose-related side-effects suggest that the current dose (12 mg plus 12 mg, 24 h apart) might be too high. We therefore investigated whether a half dose would be non-inferior to the current full dose for preventing respiratory distress syndrome.MethodsWe designed a randomised, multicentre, double-blind, placebo-controlled, non-inferiority trial in 37 level 3 referral perinatal centres in France. Eligible participants were pregnant women aged 18 years or older with a singleton fetus at risk of preterm delivery and already treated with the first injection of antenatal betamethasone (11·4 mg) before 32 weeks’ gestation. We used a computer-generated code producing permuted blocks of varying sizes to randomly assign (1:1) women to receive either a placebo (half-dose group) or a second 11·4 mg betamethasone injection (full-dose group) 24 h later. Randomisation was stratified by gestational age (before or after 28 weeks). Participants, clinicians, and study staff were masked to the treatment allocation. The primary outcome was the need for exogenous intratracheal surfactant within 48 h after birth. Non-inferiority would be shown if the higher limit of the 95% CI for the between-group difference between the half-dose and full-dose groups in the primary endpoint was less than 4 percentage points (corresponding to a maximum relative risk of 1·20). Four interim analyses monitoring the primary and the secondary safety outcomes were done during the study period, using a sequential data analysis method that provided futility and non-inferiority stopping rules and checked for type I and II errors. Interim analyses were done in the intention-to-treat population. This trial was registered with ClinicalTrials.gov, NCT02897076.FindingsBetween Jan 2, 2017, and Oct 9, 2019, 3244 women were randomly assigned to the half-dose (n=1620 [49·9%]) or the full-dose group (n=1624 [50·1%]); 48 women withdrew consent, 30 fetuses were stillborn, 16 neonates were lost to follow-up, and 9 neonates died before evaluation, so that 3141 neonates remained for analysis. In the intention-to-treat analysis, the primary outcome occurred in 313 (20·0%) of 1567 neonates in the half-dose group and 276 (17·5%) of 1574 neonates in the full-dose group (risk difference 2·4%, 95% CI –0·3 to 5·2); thus non-inferiority was not shown. The per-protocol analysis also did not show non-inferiority (risk difference 2·2%, 95% CI –0·6 to 5·1). No between-group differences appeared in the rates of neonatal death, grade 3–4 intraventricular haemorrhage, stage ≥2 necrotising enterocolitis, severe retinopathy of prematurity, or bronchopulmonary dysplasia.InterpretationBecause non-inferiority of the half-dose compared with the full-dose regimen was not shown, our results do not support practice changes towards antenatal betamethasone dose reduction