Publications

Abstract

Background: To investigate the impact of maximal ventricular dilatation and age at first neurosurgical intervention on neurodevelopmental impairment among preterm newborns with post-hemorrhagic ventricular dilatation (PHVD).

Methods: Retrospective cohort study of 105 surviving newborns ≤34 weeks’ gestation between 2012-2020 with PHVD. We studied the association of maximal ventricular dilatation to significant impairment at 18-months corrected-age in the overall cohort and of ventricular dilatation and timing of first neurosurgical intervention to impairment in the 51 newborns who underwent a neurosurgical intervention.

Results: Forty-nine of 105 (47%) had significant impairment. Maximal anterior horn width (AHW) but not ventricular index was associated with significant impairment (adjusted odds ratio [aOR] 2.07, 95%CI 1.18-3.65 for AHW quintiles) after adjusting for site, GA, intraventricular hemorrhage grade, and neurosurgical intervention. In the 51 (49%) newborns that underwent neurosurgical intervention, the first neurosurgical intervention occurred at median 23 days of life (IQR 17,40). Only age >23 days at first intervention was associated with significant impairment after adjusting for AHW and GA (aOR 6.32, 95%CI 1.13-35.29).

Conclusion: Increasing maximal ventricular dilatation and later age at first neurosurgical intervention were associated with significant impairment in preterm PHVD survivors. Intervening promptly upon progression of severe PHVD may mitigate later impairment.

Impact: The combined impact of maximal ventricular dilatation and timing of intervention in post-hemorrhagic ventricular dilatation (PHVD) is not well-established. Greater maximal anterior horn width but not ventricular index was associated with significant impairment. In those receiving a neurosurgical intervention, later age at first intervention was associated with significant impairment. Intervening promptly upon progression of severe PHVD may mitigate later impairment.

Abstract

Objective: Little is known regarding the safety of ifosfamide in pregnant women and some case reports were associated with oligohydramnios. In the study, we performed a comprehensive analysis of the available data regarding the safety of ifosfamide in pregnant women.

Material and methods: First, we performed a case-by-case review of the cases related to ifosfamide use during pregnancy that were spontaneously reported in the French Pharmacovigilance Database. Second, we reviewed cases from the literature. Finally, we performed a disproportionality analysis on VigiBase, the WHO global safety database (VigiBase), to assess the association between ifosfamide and selected adverse events in pregnant women.

Results: A total of 27 cases of ifosfamide use during pregnancy were identified. No congenital malformation was reported. Main adverse events were intrauterine growth restriction (n = 15, 56 %) and oligohydramnios or anhydramnios (n = 15, 56 %). Pregnancy resulted in intrauterine fetal death in 5 (19 %) cases, all being treated with ifosfamide before the 21th week of gestation. All livebirths (n = 22) were preterm, associated with neonatal acute renal failure in 5 (23 %) cases. In addition, 3 (14 %) neonatal deaths were reported within the first week of life in neonates having anuria. In VigiBase, which has over 263,145 spontaneous safety reports related to pregnancy, we found a significant increased reporting of oligohydramnios, intrauterine growth restriction and neonatal acute renal failure with ifosfamide compared to other antineoplastic agents.

Conclusion: Altogether, this comprehensive analysis supports that ifosfamide may induce fetal nephrotoxicity in pregnant women. It can result in intrauterine growth restriction, oligohydramnios and neonatal acute renal failure, as well as fetal death especially for early exposure during the first half of pregnancy.

Keywords: Doxorubicin; Ifosfamide; Intrauterine growth restriction; Oligohydramnios; Pharmacovigilance; Pregnancy; Renal failure; Sarcoma.

Abstract

Objective: To examine the relationship between etiologically-based preterm birth sub-groups and early postnatal growth according to gestational age at birth.

Methods: Prospective, multinational, cohort study involving 15 hospitals that monitored preterm newborns to hospital discharge. Measures/exposures: maternal demographics; etiologically-based preterm birth sub-groups; very, moderate and late preterm categories, and feeding.

Primary outcomes: serial anthropometric measures expressed as z-scores of the INTERGROWTH-21^st preterm postnatal growth standards.

Results: We included 2320 singletons and 1180 twins: very=24.4% (n = 856, including 178 < 28 weeks’ gestation); moderate=16.9% (n = 592) and late preterm=58.6% (n = 2052). The median (interquartile range) postmenstrual age at the last measure was 37 (36-38) weeks. The ‘no main condition’ sub-group percentage increased from early to late preterm; the ‘perinatal sepsis’ sub-group percentage decreased. ‘Perinatal sepsis’, ‘suspected IUGR’ and ‘fetal distress’ very and late preterm infants had lower postnatal growth patterns than the ‘no main condition’ reference sub-group. This pattern persisted in late but not very preterm infants when postnatal growth was corrected for weight z-score at birth.

Conclusion: The proportional contribution of etiologically-based preterm sub-groups and their postnatal growth trajectories vary by preterm category. Postnatal growth is partially independent of fetal growth in the majority of preterm infants (i.e., those born late preterm).

Impact: Preterm birth, the leading cause of under-5 mortality, is a highly heterogenous syndrome, with surviving infants at risk of suboptimal growth, morbidity, and impaired neurodevelopment. Both the proportional contribution of etiologically-based sub-groups and their postnatal growth trajectories vary by preterm category (very/moderate/late). The ‘perinatal sepsis’, ‘suspected IUGR’ and ‘fetal distress’ sub-groups amongst very and late preterm infants had lower postnatal growth than the ‘no main condition’ preterm infants. The pattern persisted after adjusting for birth size only in the late preterms. Postnatal growth is partially independent of fetal growth in the majority of preterm infants (i.e., those born late preterm).

Abstract

Prophylactic administration of low-dose hydrocortisone, at replacement dosage, targets inability of extremely low gestational age neonates (ELGANs) to respond to postnatal stress due to adrenal glands immaturity and is intended to prevent serious complications such as death and bronchopulmonary dysplasia (BPD). Increasing evidence from systematic reviews shows that prophylactic hydrocortisone reduces pre-discharge mortality, improves survival without BPD, favors patent ductus arteriosus (PDA) closure, and may have beneficial effects on cardiovascular stability and urine output. In contrast, an increased risk of spontaneous intestinal perforation when prophylactic hydrocortisone is combined with indomethacin and late-onset sepsis, particularly in infants of 24-25 weeks of gestation, have been reported as major adverse events. No significant negative impact on long-term neurodevelopmental outcomes following prophylactic hydrocortisone exposure was observed. Recent real-world data, despite their intrinsic methodological limitations, generally confirm the benefits observed in clinical trials, even with additional potential benefits and without increased adverse events. Ongoing challenges and questions discussed in this invited review relate to the best population to treat, optimal timing and duration of treatment, and potential barriers to implementation due to evolving knowledge and guidelines. IMPACT STATEMENT: Prophylactic low-dose hydrocortisone improves survival without BPD in infants born extremely preterm. Recent real-world data generally confirm the benefits observed in clinical trials, even with additional potential benefits and without increased adverse events. Unanswered questions remain about optimal timing and duration of treatment, and potential barriers to implementation due to evolving knowledge and guidelines.

Abstract

Objective: The objective is to evaluate changes in survival to discharge of liveborn infants less than 32 weeks’ gestational age (GA) in France, where the latest available data on very preterm survival at a national-level are from the EPIPAGE-2 (Etude épidémiologique sur les petits âges gestationnels) cohort in 2011.

Design: Population-based cohort study.

Setting: Metropolitan France in 2011, 2015 and 2020.

Patients: All births between 22 and 31 weeks’ GA using the EPIPAGE-2 cohort study for the year 2011 and hospital discharge data linked to death certificates from the Système National des Données de Santé for the years 2015 and 2020.

Main outcome measures: The primary outcome was survival to hospital discharge among liveborn infants. Survival rates were compared using modified Poisson regression and adjusted for population characteristics (maternal age, multiple birth, sex, small for GA). Data on all births were examined to assess changes to the live birth rate.

Results: Survival to discharge among live births increased at 23 and 24 weeks’ GA from 1% and 31% in 2011 to 8% and 37% in 2015 and to 31% and 47% in 2020, respectively. From 25 to 28 weeks’ GA, survival rates tended to increase, but differences were not significant, and survival rates were stable from 29 to 31 weeks GA. Results were similar after adjustment. The proportion of live births versus stillbirths increased from 22 to 24 weeks’ GA.

Conclusion: Survival rates among live births improved between 2011 and 2020 from 23 to 28 weeks’ GA, with marked changes at 23 and 24 weeks’ GA.

Abstract

Objective: The objective is to evaluate changes in survival to discharge of liveborn infants less than 32 weeks’ gestational age (GA) in France, where the latest available data on very preterm survival at a national-level are from the EPIPAGE-2 (Etude épidémiologique sur les petits âges gestationnels) cohort in 2011.

Design: Population-based cohort study.

Setting: Metropolitan France in 2011, 2015 and 2020.

Patients: All births between 22 and 31 weeks’ GA using the EPIPAGE-2 cohort study for the year 2011 and hospital discharge data linked to death certificates from the Système National des Données de Santé for the years 2015 and 2020.

Main outcome measures: The primary outcome was survival to hospital discharge among liveborn infants. Survival rates were compared using modified Poisson regression and adjusted for population characteristics (maternal age, multiple birth, sex, small for GA). Data on all births were examined to assess changes to the live birth rate.

Results: Survival to discharge among live births increased at 23 and 24 weeks’ GA from 1% and 31% in 2011 to 8% and 37% in 2015 and to 31% and 47% in 2020, respectively. From 25 to 28 weeks’ GA, survival rates tended to increase, but differences were not significant, and survival rates were stable from 29 to 31 weeks GA. Results were similar after adjustment. The proportion of live births versus stillbirths increased from 22 to 24 weeks’ GA.

Conclusion: Survival rates among live births improved between 2011 and 2020 from 23 to 28 weeks’ GA, with marked changes at 23 and 24 weeks’ GA.

Abstract

Humans are inevitably exposed to micro- and nanoplastics (MP/NP). These particles are able to cross the biological barriers and enter the bloodstream with levels close to 1.6 µg mL⁻¹; MP/NP have been detected in placentas and meconium of newborns. However, the consequences of this exposure on the integrity, development and functions of the human placenta are not documented. In this study, trophoblasts purified from human placentas at term were exposed for 48 h, to two different sizes of polystyrene nanoparticles (PS-NP) of 20 nm (PS-NP₂₀) and 100 nm (PS-NP₁₀₀), at environmental and supra-environmental concentrations (0.01–100 µg mL⁻¹). Cell viability, oxidative stress, mitochondrial dynamics, lysosomal degradation processes, autophagy, inflammation/oxidative responses and consequences for placental endocrine and angiogenic functions were assessed. PS-NP size determines their internalization rate and their behavior in trophoblasts. Indeed, PS-NP₂₀ are more rapidly translocated, and accumulated in lysosomes as shown by confocal and TEM imaging. They induce higher cytotoxicity than PS-NP₁₀₀, as early as 1 µg mL⁻¹ (p < 0.05). In addition, they induce a pro-inflammatory cytokines response: IL-1ß is induced from 0.01 µg mL⁻¹ for the both nanoparticle sizes; IL-6, and TNF-α are overexpressed at 100 µg mL⁻¹ only for PS-NP₂₀ (p < 0.05). For the first time, we report that PS-NP disrupt endocrine function, as observed by a decreased hCG release at concentrations found in human blood. This work, provides an in-depth in vitro assessment of the effects of PS-NP on the human placenta.

Abstract

Bronchopulmonary dysplasia (BPD) is a serious complication of extreme prematurity and has few treatment options. The postnatal use of steroids to prevent BPD remains controversial, but prophylactic low-dose hydrocortisone (HC) has been shown to improve survival without BPD. However, an increased risk of late-onset sepsis (LOS) was also reported in extremely preterm neonates exposed to prophylactic HC treatment. Because its causal link remains unclear, our objective was to assess the effect of prophylactic HC exposure on LOS risk, adjusted for perinatal risk factors of LOS. We re-analyzed the PREMILOC trial to investigate the postnatal factors influencing the incidence of LOS occurring after day 3 from baseline conditions and to evaluate the potential interaction produced by prophylactic HC exposure. We used three different statistical models (poisson, Cox regression, competing risks) to test the effect of HC on LOS occurrence. LOS was reported in 64/264 (24%) and 77/255 (30%) in the placebo and HC groups, respectively (P = 0.12). A decreasing risk of LOS was observed with increasing gestational age (P < 0.001), vaginal delivery (P = 0.005), and supplemental corticosteroids given after a 10-day treatment with prophylactic HC but before the LOS (P < 0.001). A trend of higher risk of LOS was noted in infants exposed to perinatal asphyxia (P = 0.065). Adjusted for these covariates, we found a non-significant association between HC exposure and risk of LOS (relative risk, 1.041 (95% CI, 0.738 to 1.471]), P = 0.817). Using a survival competing risk analysis, we confirmed the lack of significant effect of HC on LOS (hazard risk ratio, 1.105 [95% CI, 0.787 to 1.552], P = 0.560), while competing death was significantly reduced by the treatment (hazard risk ratio, 0.427 [95% CI, 0.259 to 0.707], P < 0.001).

Conclusion: The effect of prophylactic HC compared with placebo on LOS is summarized by a risk ratio varying within the interval [0.90-1.10] and this effect was never significant.

Trial registration: EudraCT number 2007-002041-20, ClinicalTrials.gov number NCT00623740.

Abstract

Background: Machine-learning methods are gaining in popularity to predict medical events but their added value to other methods is still to be determined. We compared performances of clinical prediction models for bronchopulmonary dysplasia (BPD) or death in very preterm infants using logistic regression and random forests methods.

Methods: Two population-based cohorts of very preterm infants were used: EPIPAGE-2 (France, 2011) for development and internal validation and EPICE (Europe, 2011) for external validation. Eligible infants were born before 30 weeks’ gestation and admitted in neonatal units. BPD was defined as any respiratory support at 36 weeks postmenstrual age. Candidate predictors were available shortly after birth or at day 3. Logistic regression and random forest models performance was assessed in terms of discrimination (c-statistic) and calibration plots.

Results: Prevalence of BPD/death was 32.1% (668/1923) in EPIPAGE-2 and 41.0% (1368/3335) in EPICE. At both time points, logistic regression and random forest models showed similar performance during internal validation. At birth, external validation in EPICE showed good discrimination (logistic regression model: c-statistics 0.81, 95% CI 0.80-0.83; random forest: 0.80, 95% CI 0.79-0.81) but both models underestimated the probability of BPD/death. Model performances were heterogeneous throughout European regions.

Conclusions: Both modelling methods performed similarly to predict BPD/death shortly after birth in very preterm children

Impact: Whether machine-learning methods predict better short-term respiratory outcomes in very preterm infants than logistic regression models is debated. Random forest-based prediction models did not perform better than logistic regression to predict bronchopulmonary dysplasia or death shortly after birth in very preterm infants. Calibration performances varied among European countries. While offering the same performance, regression models are easier to understand, to disseminate and to apply to different populations.

Abstract

Background: Compromised myocardial function and persistent elevated pulmonary vascular resistance are common among neonates treated with therapeutic hypothermia (TH) for hypoxic-ischemic encephalopathy (HIE). There is a lack of data regarding persistence of cardiac alterations after discharge from the neonatal intensive care unit (NICU).

Methods: We assessed cardiovascular profiles after NICU discharge. Echocardiogram data, including speckle-tracking echocardiography (STE), were extracted from the latest outpatient scan. Data were compared by initial amplitude-integrated encephalography (aEEG) profiles on admission [normal vs. abnormal].

Results: In total, 70 (19%) neonates had a follow-up echocardiogram (22 with initial normal aEEG, 48 with abnormal aEEG). Age at follow-up was similar between the two groups (6.2 vs. 7.7 months, [p = 0.08]). Neonates with an initially abnormal aEEG showed more negative Right Ventricle (RV)-peak global longitudinal strain (-28.2 vs. -26.0%, [p = 0.02]), RV-peak free wall longitudinal strain rate (-1.24 vs. -1.10 [1/second], [p = 0.01]), and RV-peak free wall longitudinal strain rate (-1.50 vs. -1.27 [1/second], [p = 0.001]). These associations remained after multilinear regression analysis, indicating persistent enhanced RV contraction in the abnormal aEEG group.

Conclusion: Neonates with initial abnormal aEEG profiles exhibited increased RV contraction after NICU discharge. Future studies should explore long-term cardiovascular follow-up of neonates with HIE, beyond the perinatal period.

Impact: What is the key message of your article? Cardiac performance in hypoxic ischemic encephalopathy is linked to adverse outcomes. Survivors with an abnormal aEEG at admission showed increased right ventricular contractility at follow-up, possibly related to an adverse adaptation to the initial insult. What does it add to the existing literature? This study offers insights into long-term cardiovascular outcomes in neonates with HIE, focusing on the link between initial aEEG abnormalities and later RV function. What is the impact? The findings underscore the importance of early cardiovascular assessments and monitoring in neonates undergoing TH for HIE, potentially guiding future follow-up protocols.