Publications

Abstract

Necrotizing enterocolitis (NEC) is probably the most painful intestinal disease affecting infants born preterm. NEC is known to cause highly severe and prolonged pain that has been associated with adverse short- and long-term effects. However, research on pain management in infants with NEC is scarce. This is likely due to its low incidence and very acute occurrence. As a result, the optimal pain management for these vulnerable infants remains unknown, and analgesic therapy practices are highly variable. Therefore, we aimed to establish expert-based consensus recommendations on pain management for NEC. Experts of the European Society for Paediatric Research (ESPR) Special Interest Groups on Neonatal pain and NEC were invited to participate in two consensus meetings. Prior to the first hybrid consensus meeting, an online survey provided input for potential recommendations. During the consensus meetings, experts shared clinical expertise and voted on recommendations. An expert consensus statement, comprising nine recommendations on optimal pain assessment and pain treatment in infants with NEC, was developed. Expert recommendations included regular pain assessments with a neonatal pain scale with additional assessments on indication and pre-emptive administration of analgesic therapy (e.g., paracetamol and an opioid) in infants with NEC stage ≥ II.

Conclusion: This expert consensus statement provides clinical recommendations essential for any healthcare professional caring for premature infants with NEC. The recommended guidance this statement provides on pain management strategies is key to preventing and reducing pain in this vulnerable population.

What is known: • Necrotizing enterocolitis (NEC) is a very painful disease, making effective pain management essential. • Current pain management practices for infants with NEC are highly variable.

What is new: • This expert consensus statement provides recommendations on optimal pain assessment and pain treatment in infants with NEC. • These clinical recommendations may help better prevent pain in these vulnerable infants.

Abstract

Results: in both cohorts, treatment with inhaled nitric oxide was not associated with IQ at age 5–6 years. Analysis identified maternal educational level, gestational age at discharge from hospital, intraventricular haemorrhage and maternal country of birth as important factors associated with IQ scores.

Aim : To investigate whether treatment with inhaled nitric oxide is associated with cognitive performance at age 5–6 years in preterm-born children.

Methods : we analysed preterm children from two large European cohort studies, the German Neonatal Network (GNN) (N = 3606) and the French EPIPAGE-2 cohort (N = 2579) admitted to neonatal care and followed up at age 5–6 years. Both cohorts had recorded data on iNO treatment. General cognitive ability was tested with IQ tests. Classification and Regression trees analysis was used to identify prenatal, perinatal and neonatal, clinical and social-environmental predictors of IQ.

Conclusion : Treatment with inhaled nitric oxide was neither negatively nor positively associated with IQ at age 5–6 years. Neonatal and brain health, as well as socioeconomic factors are important for cognitive performance in early childhood.

Abstract

Zika virus (ZIKV) is a neurotropic virus that can be transmitted congenitally. In ZIKV-infected pregnant women, placental dysfunction is associated with the secretion of nonstructural protein 1 (NS1). In this study, the kinetics of NS1 secretion and antibody response were assessed and characterized in the serum of ZIKV-positive adult patients recruited in French Guiana. NS1 concentrations were quantified by a single molecule array (SiMoA) in 164 sequential serum samples collected from thirty patients during the first month after onset of symptoms. Serum NS1 concentrations in this cohort were unexpectedly low and ranged from 0.1 pg/mL to 380 pg/mL. The median persistence of NS1 in patients with a clinical score of 2 (6 days) was significantly lower than in patients with a clinical score of 3 (8 days). In both groups of patients, anti-NS1 IgM and IgG kinetics were similar but patients with a milder clinical score of 2 had statistically higher levels of specific IgM than those with a clinical score of 3. Herein, it was shown that NS1 circulating in patient sera is associated with clinical outcome, emphasizing the role of NS1 in ZIKV pathogenesis.

Abstract

Background: The objective of this study was to evaluate total circulating PlGF (placental growth factor) and free PlGF concentrations to provide insights into the mechanisms of decreased PlGF noted in preeclampsia and fetal growth restriction.

Methods: We conducted a retrospective single-center study in pregnant women receiving care for suspected preeclampsia or fetal growth restriction. Serum angiogenic proteins (sFLT1 [soluble fms-like tyrosine kinase] and free PlGF) were measured on an automated platform as part of standard-of-care. Total PlGF concentrations in the serum were directly measured using a validated biochemical procedure that dissociated circulating sFLT1 and PlGF complexes. Small for gestational age (SGA) was defined by birthweight ≤10th percentile.

Results: Of the 407 women studied, 155 women did not develop preeclampsia or SGA (control group), 111 women developed SGA without preeclampsia (SGA group), 71 women developed preeclampsia without SGA (preeclampsia group), and 70 developed preeclampsia and SGA (preeclampsia+SGA group). Despite reductions in free PlGF levels (229 [158-321] pg/mL), total PlGF levels were not reduced in the preeclampsia group (1020 [738-1444] pg/mL) compared with the control group (1077 [763-1595] pg/mL). In contrast, the total PlGF levels were significantly reduced in the SGA group (744 [462-1161] pg/mL; P<0.0001) and the preeclampsia +SGA group (616 [349-917] pg/mL; P<0.0001) compared with the control group (1077 [763-1595] pg/mL).

Conclusions: Placental dysfunction associated with preeclampsia, characterized by reduced free PlGF levels but unchanged total PlGF, is driven by excessive placental production of sFLT1. Placental dysfunction associated with SGA, marked by reductions in both free and total PlGF, is mediated by decreased placental PlGF production.

Abstract

Aim : infants born very preterm spend their early postnatal life in a neonatal intensive care unit, where irregular and unpredictable sounds replace the structured and familiar intrauterine auditory environment. Music interventions may contribute to alleviate these deleterious effects by reducing stress and providing a form of environmental enrichment.

Material and Methods : this was an ancillary study as part of a blinded randomised controlled clinical trial entitled the effect of music on preterm infant’s brain development. It measured the impact of music listening on the autonomic nervous system (ANS), we assessed heart rate variability (HRV) through high-resolution recordings of heart rate monitoring, at three specific postmenstrual ages in premature infants.

Results : from 29 included subjects, 18 were assessed for complete HRV dataset, including nine assigned to the music intervention and nine to the control group. Postmenstrual age appeared to be the main factor influencing HRV from 33 weeks to term equivalent age. Further analyses did not reveal any detectable effect of music intervention on ANS response.

Conclusion : this study found that ANS responses were not modified by recorded music intervention in very preterm infants during wakefulness or sleep onset. Further research is warranted to explore other factors influencing ANS development in this population.

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. © 2025 The Author(s). Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Abstract

Background: Clinical data suggest that females might be more resistant to hypoxia than males, with male sex recognized as a risk factor for suffering life-long neurological sequelae. However, the impact of hypoxia-ischemia in certain brain regions and its association with genetic sex remains unclear.

Methods: Using the piglet model of neonatal brain injury, fifteen piglets (8 females and 7 males) were subjected to a global cerebral hypoxic-ischemic insult. After 48 h, total cell death and the number of necrotic, apoptotic and cleaved-caspase-3 positive cells was quantified in five brain regions.

Results: Male piglets exposed to hypoxia-ischemia were more vulnerable than females (total cell death p < 0.01), also showing a region-specific response to brain injury depending on sex, with males being more affected in both deep gray (caudate p < 0.01; THAL p < 0.0001) and white (p < 0.01) matter. Despite necrosis was the primary form of cell death for both sexes, the pattern of cell death differed: while male piglets showed more necrosis (p < 0.0001), apoptosis (p < 0.0001) and caspase-3 activation (p < 0.0001) were higher in females.

Conclusion: Our results suggest that male piglets were globally and regionally more vulnerable than females after HI; further, both the pattern of cell death and the apoptotic molecular mechanisms were sexually dimorphic.

Impact: Clinical data suggest that females might be more resistant to perinatal asphyxia than male newborns. The impact of hypoxia-ischemia in certain brain regions and the association of cell death patterns with sex remain unclear. Hypoxic-ischemic male piglets were more vulnerable than females, showing also increased regional vulnerability in both deep gray and white matter areas. Although necrosis was the primary form of cell death for both sexes, male piglets showed more necrosis, whereas apoptosis and caspase-3 activation were higher in females. Neonatal brain injury and therapeutic responses may be sex-dependent due to differences in cell death patterns and molecular mechanisms.

Abstract

Chronic histiocytic intervillositis (CHI) is an inflammatory condition of the placenta, characterised by an abnormal, mainly macrophagic infiltrate within the intervillous space. Recent research suggests that CHI results from a ‘maternal‐foetal rejection’ mechanism, because at least some CHI cases fulfil the criteria for antibody‐mediated rejection (AMR) of kidney allografts according to the Banff classification [i.e. presence of anti‐human leukocyte antigen (HLA) paternal antibodies activating the complement or foetal‐specific antibodies (FSA), a macrophage‐rich infiltrate, and positive C4d immunostaining]. To gain further insights into CHI pathogenesis, we aimed to refine the phenotype of the inflammatory infiltrate using a multiplex immunofluorescence technique and to compare the mRNA signatures between CHI and AMR of kidney allografts. Twelve patients with C4d+ FSA+ CHI were included in the study and compared to a control group of 5 patients without inflammatory lesions on placental examination. We developed a multiplex immunofluorescence panel to identify CD4+ and CD8+ T lymphocytes, CD68+/CD206− and CD68+/CD206+ macrophages, and NK cells in the villi and intervillous space. Molecular signatures were studied using NanoString® technology and the B‐HOT panel recommended by the Banff classification for kidney allografts. Multiplex immunofluorescence revealed that the infiltrate in the intervillous space was mainly composed of CD68+/CD206− macrophages as well as a higher proportion of CD8+ lymphocytes in patients with CHI compared to controls. Densities of NK cells and CD4 T cells were very low. Molecular signatures showed an overexpression of HLA class II genes, an IFN‐γ signature, and cytokine gene sets in C4d+ FSA+ CHI patients, also involved in kidney AMR. These results reinforce the paradigm of maternal‐foetal rejection.

Abstract

Background: Before 26 weeks of gestational age, because extremely preterm infants (EPI) face a high risk of death or disability, management decisions may involve either active treatment or palliative care. Survival chances largely depend on the willingness of medical teams and parents to opt for active management. Variability of practices explains differences in survival between countries and regions, and interpersonal variability may also exist among caregivers within the same center. Our objective was to study the variability of management decisions and their determinants among caregivers in a French type 3 maternity hospital.

Methods: All caregivers, obstetricians, pediatricians, and midwives, involved in the management of EPI in a type 3 perinatal center were surveyed using a self-administered questionnaire. Each respondent reported their personal thresholds for deciding on active management, defined as the unborn child’s estimated likelihood of survival without severe neonatal morbidity. Median and interquartile ranges (IQR) of these thresholds were calculated and compared by respondent characteristics.

Results: 85 (75%) eligible professionals responded. The median threshold of survival without severe neonatal morbidity below which active management was deemed impossible was 15% (IQR 10-30%), while the median threshold above which active management could not be refused was 80% (IQR 70-90%). Wide IQRs indicated significant variability in individual thresholds. This variability appeared to be influenced by profession and gender but was not associated with factors such as having children, age, experience, or the personal estimates of the neonates’ outcomes.

Conclusions: Decision thresholds for active management of EPI, expressed in terms of survival without severe neonatal morbidity, vary significantly among professionals. The thresholds reported in our study were notably higher than those observed in other countries, which may help explain the lower rates of active management before 26 weeks in France. Recognizing these differences and comparing personal thresholds with peers could facilitate more consensus-based decision-making within teams.