Publications

ABSTRACT

Objective :To examine associations between a 5-min Apgar score < 7 and severe neonatal outcomes in very preterm (VPT) infants and how results are impacted by variations in assigning Apgar scores within an international context.

Design : Prospective observational population-based cohort study.

Setting : Eleven structurally and organisationally diverse countries across Europe.

Population : In total, 7900 liveborn VPT infants from the EPICE-SHIPS study.

Methods : Descriptive statistics, logistic regression, modified Poisson regression.

Main Outcome Measures : Associations between 5-min Apgar scores < 7 and adverse neonatal outcomes were estimated with adjustments for perinatal characteristics. We tested for interactions by country-level prevalence of an Apgar score < 7, grouped into low (14%–16%), medium (19%–22%) and high (28%–40%).

Results : 20.2% of infants had 5-min Apgar score < 7 with rates of 14%–40% across countries. A score < 7 increased risks of in-hospital mortality, intraventricular haemorrhage (IVH), cystic periventricular leukomalacia (cPVL), retinopathy of prematurity (ROP), bronchopulmonary dysplasia (BPD) and length of hospital stay (LHS), but not necrotising enterocolitis or late-onset infection (LOI). No interactions with country group were detected for mortality, cPVL and ROP, while associations with IVH, BPD and LHS were restricted to countries with lower prevalence of scores < 7.

Conclusions : Significant differences exist in the prevalence of low Apgar scores across countries. Their interactions with adverse outcomes demand caution when using the Apgar score in prognostic models for clinical care and research without local validation. More broadly, our findings emphasise the importance of accounting for country-specific effects in clinical assessment scores.

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.

Abstract

STOX1 has been involved in genetic forms of preeclampsia. The gene encodes two major isoforms coined STOX1A and STOX1B (989 and 227 amino-acids, respectively), sharing the same DNA binding domain. The two isoforms have opposite function on major genes involved in trophoblast syncytialization and oxidative stress management. Placenta-fetal overexpression of STOX1A induces preeclampsia in mice. Here we explore the effects of STOX1B placenta-fetal overexpression. A STOX1B transgenic mouse line (expression restricted to the foeto-placental unit through ad hoc crosses) was analyzed in terms of blood pressure, proteinuria, soluble antiangiogenic factors, placental and fetal weights, maternal heart weight, and placental histology. Placental gene expression was explored by RNA-sequencing, followed by a bioinformatics analysis. Female mice carrying STOX1B placentas displayed preeclampsia features with a striking increase of genes involved in coagulation, presumably under the control of the HNF4α transcription factor. Genes specific of the spongiotrophoblast were strongly down-regulated consistently with a junctional zone reduction. This new model of preeclampsia seems connected with an enhancement of coagulation processes, similar to preeclamptic patients living at high altitude. Our model could be useful to study the features of preeclampsia in this context, and be a convenient complement to other animal models of preeclampsia.

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: 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

Introduction: Acute respiratory disorders and bronchopulmonary dysplasia (BPD) are frequent and serious complications in very preterm infants (VPI). These conditions are influenced by several factors, including fluid imbalances and abnormal postnatal changes in body water composition (BWC). We aimed to investigate the association between BWC and the severity of respiratory disease in VPI using bioelectrical impedance analysis (BIA).

Material and methods: We conducted an observational study in a third-level neonatal intensive care unit at Reunion Island University Hospital. Infants born before 32 weeks of gestation, with BWC monitoring during hospital stay, were included. The severity of respiratory disease was assessed using mean airway pressure (MAP) recorded at the same time as BIA. Secondary outcomes included the Lung Ultrasound Score (LUS), measured weekly from 28 days of life, and BDP occurrence and severity at 36 weeks of postconceptional age.

Results: We included 34 VPI (BW 1,131 ± 352 g, gestational age 28.0 ± 2.2) and performed 267 BWC analyses (average: 8 BIA/patient). MAP was directly associated with extracellular water (ECW, % of body weight) (p < 0.001), even after adjustment for confounding variables at multivariate analysis (p < 0.02). No significant association was observed between total body water measures and the LUS. ECW was significantly associated with the occurrence of severe BPD (p < 0.003).

Abstract

Objective : to use the Delphi method to gain insight into approaches to prenatal diagnosis and management of preterm birth (PTB) in twin pregnancies, including complications such as twin-to-twin transfusion syndrome (TTTS) and a short and/or dilated cervix.

Methods : a three-round Delphi process was conducted among an international panel of experts to assess their approach to prevention, monitoring and management strategies for PTB in twin pregnancies. Experts were selected based on their publication record or membership of related organizations. Response options were multiple-choice answers or a five-point Likert scale. A priori, a cut-off of ≥ 70% agreement was used to define consensus.

Results : a total of 117 experts participated in the first round, of whom 94/117 (80.3%) completed all subsequent rounds. Representatives came from at least 22 countries (across five continents), most commonly the USA (50.4%) and the UK (12.0%). Over 70% of experts performed routine screening of cervical length (CL) using transvaginal ultrasound at 18–23 weeks’ gestation, using CL ≤ 25 mm to diagnose short cervix in twin pregnancies, regardless of a history of PTB. In twin pregnancies with a short non-dilated cervix, most experts offered vaginal progesterone rather than pessary or cervical cerclage, regardless of a history of PTB. In twin pregnancies with asymptomatic dilated cervix, consensus was reached (88.3% agreement) for placement of cervical cerclage, performed up to 24 weeks’ gestation (67.5% agreement; no consensus). Similarly, 96.1% of experts agreed that performing serial transvaginal ultrasound measurements of CL at 16–24 weeks’ gestation was warranted in women with a current singleton pregnancy who had a previous twin pregnancy that required physical examination-indicated cerclage; these patients should be considered high risk for PTB (83.1% agreement). In twin pregnancies with TTTS, laser surgery is offered by most experts, regardless of preoperative CL. In patients with TTTS and short CL, most experts would recommend cervical cerclage (71.9%) or vaginal progesterone (65.6%) rather than pessary or expectant management. However, no consensus was reached on measures to prevent PTB in cases of TTTS with cervical dilation.

Conclusions : This Delphi consensus study highlights practice variations among healthcare providers worldwide in the evaluation and management of PTB in twin pregnancies, which often differ from recommendations given by national and international societies.