Publications

Abstract

Background: To estimate the association between very preterm birth combined with the presence of a congenital anomaly and economic costs during the fifth year of life in Europe.

Methods: An economic analysis was embedded within a population-based prospective cohort study, including all infants born between 22 + 0 and 31 + 6 weeks’ gestation in 2011-2012 in 19 regions across 11 European countries. Economic costs (€, 2022 prices) during the fifth year of life were estimated for children born very preterm with (n = 313) and without (n = 3374) a congenital anomaly, and by severity of congenital anomaly. Multilevel generalised linear models explored factors associated with economic costs by anomaly severity.

Results: Total mean societal costs during the fifth year of life were significantly higher among very preterm children born before 32 weeks with a congenital anomaly than those without (unadjusted mean cost difference: €2760, p = 0.02). A multilevel model including socioeconomic, clinical characteristics, and complications of preterm birth, showed that total mean societal costs were €3281 higher for children born before 32 weeks with congenital anomalies compared to those without (p < 0.001).

Conclusion: Very preterm birth combined with the presence of a congenital anomaly generates significant economic costs on health and social care systems in Europe.

Impact: Very preterm birth combined with the presence of a congenital anomaly is associated with increased health and social service costs and increased societal costs during the fifth year of life. Additional severe neonatal morbidity is independently associated with increased costs in this population. Very preterm birth together with a congenital anomaly creates substantial economic burdens for health and social care systems and families five years after birth.

Abstract

Background: Preterm birth is the leading cause of death in children under five years of age worldwide. The association between preterm birth and long-term outcomes is vaguely known. In very preterm infants, the gut microbiome is highly variable and impacted by the neonatal intensive care unit environment. Our objective was to better understand the crosstalk between the gut microbiome and the host at one month of age in very preterm infants and its impact on neurological outcomes at two years of age. We performed a multi-omics analysis of fecal samples collected in 2011 from 73 very preterm French infants at one month of age, grouped according to their neurodevelopment assessed at two years of age using the Ages & Stages questionnaire. Multi-omics profiling and integrative analyses were performed between 2022 and 2023, including fecal microbiome, metabolome, and host transcriptome characterization using 16 S rRNA gene sequencing, LC-MS, and mRNA sequencing, respectively.

Results: The gut microbiome of very preterm infants at one month is mostly driven by either Escherichia or Staphylococcus, which are differentially associated with host immune markers (CAMP), metabolomic pathways, notably the energy pathway due to the presence of various nicotinamide adenine dinucleotides (NAD+) and two-year neurodevelopmental outcomes.

Conclusion: The gut microbiome at one month of age could be a noninvasive biomarker of gut immaturity and metabolic defects. Escherichia and Staphylococcus proportions were found to be the best indicators of physiological maturity and immaturity, respectively. Escherichia may help the process of intestinal maturation in preterm infants through specific metabolites production and is associated with a better neurodevelopment.

Abstract

Objectives: Bacillus cereus sensu lato (s.l.) or B. cereus group increasingly causes severe infections in preterm neonates. However, species-level identification and virulence characterization remain limited. This study aimed to identify B. cereus group species responsible for invasive infections in preterm neonates and to correlate genomic virulence profiles with clinical outcomes.

Methods: We conducted a retrospective, multicentre study across 13 French hospitals (2010-2021), including 40 B. cereus group isolates from blood or cerebrospinal fluid of preterm neonates with invasive infections. Clinical data were extracted from patient records. Whole-genome sequencing (WGS) (Illumina and Oxford Nanopore) with hybrid assemblies enabled species identification using digital DNA-DNA hybridization and average nucleotide identity. Virulence genes were screened against a curated database of 65 virulence genes, and associations with clinical outcomes were analysed.

Results: Forty isolates were analysed, 42.5% (17 of 40) of patients developed septic shock, and 37.5% (15 of 40), died, usually after rapid clinical deterioration. WGS identified seven species, predominantly Bacillus paranthracis (47.5%, 19 of 40) and B. cereus sensu stricto (20%, 8 of 40). Virulence gene content varied by species. The presence of hblCDAB (60%, 9 of 15), nprB (46.5%, 7 of 15), asbABCDEF (80%, 12 of 15), and essC-cereus/esxA (66.7%, 10 of 15) genes correlated with mortality (p 0.00015, 0.002, 0.0027, and 0.02, respectively). B. cereus sensu stricto carried more virulence determinants and was associated with higher mortality than B. paranthracis and other species, at day 7 (p 0.05) and at day 28 (p 0.0065). The cesH gene (60%, 15 of 25) is significantly associated with survival (p 0.007), particularly with B. paranthacis, the predominant species in our cohort.

Conclusions: Invasive B. cereus group infections in preterm neonates are associated with high mortality, particularly in cases due to B. cereus sensu stricto. WGS enables precise species identification and virulence profiling, which are essential insights for diagnostic refinement, outbreak control, and risk stratification in neonatal intensive care settings.

No abstract available

No abstract available

Abstract

Importance: The Apgar score, the first clinical assessment to direct measures to stabilize newborn infants, is also used for risk assessment. Its accuracy in estimating outcomes remains poor among very preterm (VPT) infants.

Objective: To assess the utility of the combined 5-minute Apgar score and umbilical artery pH (UA-pH) for estimating risks of mortality and severe neonatal morbidity among VPT infants.

Design, setting, and participants: This cohort study (Effective Perinatal Intensive Care in Europe [EPICE]) analyzed infants born at less than 32 weeks’ gestation between April 2011 and September 2012 across 11 European countries. All liveborn VPT infants with Apgar scores and UA-pH data were included. Data were analyzed between February and December 2025.

Exposures: Apgar score at 5 minutes and UA-pH. The Apgar score was classified as lower than 7 and 7 or higher, and the UA-pH values were categorized as low (<7.20) and normal (≥7.20). Four groups that combined these 2 measures were defined: Apgar score lower than 7 and low UA-pH; Apgar score lower than 7 and normal UA-pH; Apgar score 7 or higher and low UA-pH; and Apgar score 7 or higher and normal UA-pH.

Main outcomes and measures: Combined outcome of mortality and/or any adverse morbidity (intraventricular hemorrhage [IVH] >grade 2, cystic periventricular leukomalacia, moderate or severe bronchopulmonary dysplasia [BPD], retinopathy of prematurity ≥stage 2, and necrotizing enterocolitis). Modified Poisson regression was used to estimate relative risks (RRs) between the exposure and the combined mortality and morbidity outcome and 3 individual components: mortality, IVH, and BPD. Models were adjusted for perinatal variables associated with Apgar score and UA-pH and adverse neonatal outcomes.

Results: Of 7900 liveborn infants in the EPICE cohort, 4174 (52.8%) had information on Apgar score and UA-pH. These infants included 2249 males (53.9%) and had a median [IQR] gestational age of 29.9 [27.9-31.0] weeks and median [IQR] birth weight of 1240 [960-1520] g. A total of 367 infants (8.8%) had an Apgar score 7 or higher but a low UA-pH, 558 (13.4%) had an Apgar score lower than 7 but a normal UA-pH, and 196 (4.7%) had an Apgar score lower than 7 and a low UA-pH. Infants with an Apgar score lower than 7 had a higher frequency of the combined outcome among those with a normal UA-pH (270 [48.4%] vs 596 [19.5%]) and a low UA-pH (108 [55.1%] vs 596 [19.5%]), with similar adjusted RRs (ARRs; low: 1.4 [95% CI, 1.2-1.7]; normal: 1.4 [95% CI, 1.3-1.6]). For mortality risk, associations were robust for an Apgar score lower than 7 and a low UA-pH (ARR, 2.4; 95% CI, 1.7-3.3) and absent with an Apgar score of 7 or higher and a low UA-pH (ARR, 1.2; 95% CI, 0.8-1.8). IVH risk was increased in all 3 subcategories, including an Apgar score of 7 or higher with a low UA-pH (ARR, 2.0; 95% CI, 1.3-3.0). BPD risk was associated only with an Apgar score lower than 7 and a normal UA-pH (ARR, 1.4; 95% CI, 1.2-1.7).

Conclusions and relevance: In this cohort study of VPT infants, combining information on UA-pH with the 5-minute Apgar score was associated with improved accuracy in estimating the risk of some adverse outcomes-notably mortality and IVH, which occurred soon after birth. These results highlight the importance of exploring the associations of early markers of risk with neonatal mortality and key neonatal morbidities separately.

Abstract

Early microscopic-scale pericyte dysfunction contributes to the initial stages of many neurological diseases and represents a strong candidate target for therapeutic intervention. A non-invasive imaging modality able to image microvascular alterations induced by pericyte dysfunction is needed. In addition, the development of pericyte-focused therapies remains challenging due to the lack of early biomarkers of disease progression. Here we show that cerebral microvascular alterations induced by pericyte dysfunction can be characterized non-invasively in mice using functional ultrasound localization microscopy (fULM). Depletion of endothelial endoglin in adult mice as a model of hereditary haemorrhagic telangiectasia, leads to pericyte detachment in the arteriole-capillary transition (ACT) zone. Imaging reveals that arteriolar capillaries have irregular shapes, increased diameters, reduced blood speed and neurovascular uncoupling mainly localized in the ACT zone. Transforming growth factor-β signalling activator C381 restores pericyte coverage and neurovascular response. Our study underscores the potential of fULM in characterizing early microvascular alterations. As super-resolution ultrasound transitions to the clinic, our data support its future use in monitoring pericyte-focused therapies in humans.

Abstract

Importance: In randomized trials, early prophylactic hydrocortisone improved survival without bronchopulmonary dysplasia (BPD) with few adverse effects in extremely preterm infants. Large scale implementation data are needed to evaluate clinical effects and safety.

Objective: To examine the association between early prophylactic hydrocortisone and survival without BPD at 36 weeks’ postmenstrual age (PMA) in extremely preterm infants in Sweden after guideline implementation and to assess treatment safety.

Design, setting, and participants: A national historical cohort study with prospectively collected data from the Swedish Neonatal Quality register from 4 Swedish centers where hydrocortisone prophylaxis was implemented. The study included infants born between 22 and 27 weeks’ gestation between 2018 and 2023. Infants were divided into exposed and nonexposed groups according to the intention-to-treat principle.

Exposure: Hydrocortisone, 1 mg/kg/d, for the first 7 days of life, followed by 0.5 mg/kg/d from days 8 through 10.

Main outcomes and measures: The primary outcome was survival without BPD at 36 weeks’ PMA. A predefined statistical analysis plan with logistic regression was used to calculate unadjusted and adjusted odds ratios.

Results: Among 1106 infants (median [IQR] gestational age, 25 weeks, 6 days [24 weeks, 3 days to 27 weeks]; median [IQR] birth weight, 780 [610-964] g), 474 received hydrocortisone prophylaxis and 632 did not. Survival without BPD occurred in 154 of 474 exposed (32.5%) and 185 of 632 nonexposed (29.3%) infants (adjusted odds ratio, 1.62; 95% CI, 1.16-2.27). BPD occurred in 233 exposed (49.2%) and 345 nonexposed (54.6%) infants (adjusted odds ratio, 0.65; 95% CI, 0.49-0.86). Death before 36 weeks’ PMA occurred in 87 exposed (18.4%) and 102 nonexposed (16.1%) infants. Late-onset bacterial infection was more common in exposed infants, but not significant after adjustment. No other severe neonatal morbidities differed significantly between the 2 groups.

Conclusions and relevance: In this cohort study of extremely preterm infants, the introduction of prophylactic hydrocortisone was associated with increased survival without BPD, after adjusting for covariates. There was no significant increase in severe neonatal morbidities, except that late-onset bacterial infection was more common in the exposed group before adjustments.

Abstract

Background: Very preterm birth (<32 weeks gestation, VP), immigrant background, and language barriers are all independently associated with a high risk for mental health problems in childhood, but research has neglected the long-term development of immigrant children born VP. We assessed whether behavioural and socio-emotional problems of 5-year-old children born VP growing up across different language contexts in the European Union are associated with an immigrant background and linguistic distance of families’ mother tongue (L1) to the host countries’ official languages.

Methods: Data are from a population-based cohort including all VP births in 2011/12 in 11 European countries; a total of 3,067 children were followed up at 2 and 5 years of age. Behavioural and socio-emotional difficulties were assessed using the parent-reported Strengths and Difficulties Questionnaire (SDQ).

Results: Mixed-effects models showed that a larger linguistic distance of children’s L1 to the host countries’ official language was associated with higher SDQ total scores (0.02 [0.01, 0.03]), after adjusting for a wide range of social risks, biological, and perinatal clinical factors.

Conclusion: Language barriers in the form of linguistic distance between VP children’s L1 and countries’ official languages play a critically important role for the behavioural and socio-emotional development of immigrant children born VP.

Impact: Immigrant children born very preterm across Europe face systemic inequalities such as language barriers. Language barriers can be operationalised as a continuous linguistic distance score between children’s mother tongues and countries’ official languages. Linguistic distance plays an important role for the behavioural and socio-emotional development of immigrant children born VP. Research, policy, and practice need to better account for language barriers to increase equity in health and education.