Publications

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

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.

ABSTRACT

Background : population-based data are needed to reliably assess the impact of SARS-CoV-2 infection during pregnancy.

Objectives : to estimate the population-based incidence of SARS-CoV-2 infection and its severe forms in the obstetric population, identify risk factors of severe SARS-CoV-2 infection (severe COVID-19) and describe delivery, maternal and neonatal outcomes by disease severity, using a definition of severity based on organ dysfunction.

Methods : a prospective population-based study conducted over the three first pandemic waves between March 2020 and April 2021 in 281 maternity hospitals in six French regions included all women with SARS-CoV-2 infection during pregnancy or within 7 days post-partum, whether symptomatic or not, hospitalised or not. Severe COVID-19 forms were defined a priori using clinical, biological and management criteria of organ dysfunction. We calculated infection and severe infection rates and studied associations between sociodemographic, medical and pregnancy characteristics and severe COVID-19 by univariate and multivariate modified Poisson regression modelling.

Results : from a population of 385,214 deliveries in the participating regions, 6015 women with SARS-CoV-2 infection were identified, including 337 severe cases. The rates of severe COVID-19 were 1.1, 0.9 and 3.6 per 1000 deliveries during the first, second and third pandemic waves, respectively, and the proportions of severe COVID-19 were 8.6%, 3.4% and 9.3%, respectively. On multivariate analysis, the risk of severe COVID-19 was associated with younger and older age, migrant status, living with > 4 people, overweight or obesity, chronic hypertension or diabetes and infection ≥ 22 weeks of gestation rather than earlier in pregnancy. Neonatal morbidity occurred mostly with severe maternal infection.

Conclusion : Using an organ-based definition of severity and population-based data, rates of severe COVID-19 appeared lower than in previous studies. A permanent perinatal surveillance system is needed to assess efficiently and rapidly the impact of future pandemics.

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

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

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.