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

Objective: To estimate socio-economic (SES) inequalities in stillbirth and preterm birth rates across European countries using population-based routine data.

Design: Cross-sectional study of national-level perinatal health and SES indicators (mother’s education/occupation or area-level deprivation).

Setting: Twenty-four countries in the Euro-Peristat network.

Population: Seventeen million births in 2015-2019.

Methods: Rates of stillbirth, singleton very preterm birth (VPB) and singleton moderate/late preterm birth (MLPB) were derived from routine national birth data collected with a common protocol.

Main outcome measure: Percentage of excess adverse outcomes associated with SES and concentration indices.

Results: Median rates of adverse outcomes were higher in the lowest versus highest SES groups [Stillbirth: 4.9 (interquartile range (IQR):4.30-5.80)] versus 2.7 (IQR:2.25-3.14) per 1000 births; VPB: 1.0 (IQR: 0.87-1.12) versus 0.6 (IQR: 0.59-0.66) per 100 live births; MLPB: 5.8 (IQR: 5.27-6.40) versus 4.4 (IQR:4.13-4.65) per 100 live births. Excess adverse outcomes associated with lower SES varied greatly, particularly for stillbirth (range-3%, 51%) versus VPB (7%, 27%) and MLPB (5%, 20%). Concentration indices further highlighted varying socio-economic inequalities across countries. Median concentration indices were similar for countries with both lower and higher levels of adverse events, with median CIs of -0.12 for countries with both high and low levels of stillbirth.

Conclusion: We identified widespread but varying inequalities between countries. These seemed to be unrelated to the rate of adverse outcomes. This suggests the need for policy strategies directly targeted to the prevention of stillbirth and preterm birth in low SES populations. Our findings demonstrate the feasibility of monitoring inequalities internationally using routine data to identify effective action

Abstract

Purpose: The SEV-IDF programme aims to track infants born before 33 weeks of gestation, with very low birth weight (VLBW), neonatal encephalopathy or severe birth anomalies and perinatal disease. It employs an open, prospective, multicentric, population-based cohort approach. This report aims to describe the methodology employed to establish and manage the programme, details regarding follow-up procedures, baseline characteristics of the included infants, and highlights new research opportunities emerging from the « Suivi des Enfants Vulnérables d’Ile-de-France » (SEV-IDF) programme.

Participants: The programme aims to (1) detect developmental anomalies early, (2) improve prevention using standardised data, (3) optimise follow-up care and (4) support multidisciplinary research.Eligible participants are infants alive at discharge from the 59 maternities with a neonatal unit of the Île-de-France (IDF) region (France). A network of 567 trained physicians monitors the children’s development at 4 months, 1 and 2 years of corrected age, and 3, 4, 5, 6 and 7 years of age. Collected data include sociodemographic, pregnancy and neonatal characteristics, and standardised child development scores.

Findings to date: The programme enrolled 21 175 participants between 2016 and 2023, with 16 461 (77.7%) having a gestational age less than 33 weeks, 1916 (9.0%) others having VLBW, 1525 (7.2%) having encephalopathy and 1273 (6.0%) having another severe birth anomaly.

Future plans: The collected data will enable the SEV-IDF scientific committee to describe high-risk infants in the IDF region, design evidence-based campaigns to improve the quality and effectiveness of the follow-up as well as conduct research on developmental anomalies in these high-risk infants. Ongoing research currently focuses on anticipating loss to follow-up and early detection of developmental anomalies.

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

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.