Publications

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

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

This nationwide cohort study provides a comprehensive overview of maternal and perinatal outcomes associated with sickle cell disease (SCD) during pregnancy. Using the French national health database, all singleton pregnancy-related hospital discharges from 2013 to 2020 in women aged 15–55 (n = 5 752 080) were selected. Of these, 1022 births were to women with SCD, 308 of whom were on long-term treatment, that is, hydroxyurea (HU) and/or transfusion programme. Pregnancies with SCD were more likely to involve pre-eclampsia (9.6% vs. 1.7%; p < 0.001), pulmonary embolism (0.70% vs. 0.02%; p < 0.001), caesarean sections (52.8% vs. 18.2%; p < 0.001) and postpartum haemorrhage (8.3% vs. 4.1%; p < 0.001) compared to pregnancies without SCD. Preterm birth (<37 weeks) was much more common in women with SCD (28.5% vs. 5.6%). Infants born to women with SCD faced greater adverse neonatal outcomes (22.4% vs. 8.0%; p < 0.001). Although untreated SCD was linked to fewer complications than long-term treated SCD, both conditions presented greater risks compared with pregnancies without SCD. Unexpectedly, babies born to women with SCD had a higher incidence of congenital abnormalities (6.3% vs. 3.4%; p < 0.001), not attributed to HU use. Overall, despite advances in SCD management, pregnancy in SCD remains a high-risk condition, for both mothers and babies.

Abstract

Introduction: the literature extensively documents neonatal and paediatric outcomes related to preterm delivery,
but maternal health in this circumtances remains underexplored.
This study aimed to identify women with antepartum severe maternal morbidity (SMM) among those delivering
preterm and explore whether they delivered in hospitals with risk-appropriate maternal care facilities.
Material and methods: Women giving birth at 22–34 weeks of gestation were identified from the French national
prospective EPIPAGE-2 cohort study in 2011; terminations of pregnancy for fetal congenital malformations were
excluded. Antepartum SMM was defined as a composite outcome of severe maternal morbid events preceding
labour onset or the delivery decision. We described antepartum SMM and compared women with and without
SMM regarding the characteristics of the hospital of delivery.
Results : among 5,690 women included, 886 (16.0 %, 95 % CI, 14.7, 17.0) experienced antepartum SMM, pri-
marily due to severe pregnancy-related hypertensive disorders or major obstetric bleeding. Women with ante-
partum SMM were more likely to deliver in level III maternity units (level of neonatal care) compared with
women without antepartum SMM (68.0 % vs 59.3 %, P < 0.001). However, 18.3 % of women with antepartum
SMM delivered in hospitals without an onsite adult critical care unit, a proportion not significantly different from
those without SMM (22.0 %, P = 0.23).
Conclusions : antepartum SMM affected one in six women delivering at 22–34 weeks’ gestation. Many did not
deliver in hospitals equipped with adult critical care unit. Delivery locations for women with SMM at risk of
preterm birth should address the needs of both the mother and the newborn.

Abstract

Objective: to determine whether pulmonary hypertension (PH) is associated with higher risk of adverse neuro-
developmental outcome at age 5 in a population-based cohort of 22–31+6 preterm children.
Study design : in the EPIPAGE-2 French prospective population-based cohort of preterm children born in 2011, the neurodevelopmental outcome of children with PH was collected at 5 years. The primary outcome was a com-
posite measure with four levels of neurodevelopmental disabilities: severe, moderate, mild, no disability, based
on cerebral palsy, visual, hearing or cognitive deficiencies, behavioral difficulties and developmental coordi-
nation disorders. Secondary outcomes were autism spectrum disorders and school attendance. Missing data were multiply imputed. Developmental measures were compared using generalized estimating equations models.
Results : Of the 3007 eligible children, 1825 were analyzed, of whom 79 (4.3 %) were PH+. At age 5, 36.9 % (95
% CI, 26.0–47.8) of PH + children had moderate to severe overall neurodevelopmental disabilities compared
with 17.9 % (95 % CI, 16.1–19.8) of PH–children, P < 0.001. Significant differences at 5 years between the PH+
and PH– groups were observed for cerebral palsy (CP) (6 % versus 2.3 % for severe CP, P = 0.003), cognitive
deficiency (31.7 % versus 15.0 %, P < 0.001) and developmental coordination disorders (27.1 % versus 11.7 %,
P < 0.001). There were no significant differences in behavioral difficulties and autism spectrum disorders.
Normal school was attended by 69.2 % of PH + children versus 88.3 % of PH– children.
Conclusion : In this nationwide population-based cohort of extremely preterm and very preterm infants, moderate to severe overall neurodevelopmental disability at age 5 was significantly associated with neonatal PH.

Abstract

Background and objectives: Genetic primary microcephaly (PM) is a defect in early brain development leading to congenital microcephaly, mostly recessively inherited, and mild-to-moderate intellectual disability. PM has been largely elucidated, thanks to exome and genome sequencing. However, radial microbrain, the most severe form of genetic PM or micrencephaly described in the 1980s, which leads to early lethality or very severe intellectual handicap, remains without a molecular diagnosis. We sought to identify the cause of radial microbrain by analyzing the genotype of children/adults and fetuses with an extremely small brain.

Methods: We searched for individuals with the smallest head circumference among patients with a confirmed diagnosis of PM included in 2 French and European observational studies coordinated at the Robert Debré Children’s Hospital in Paris. Their neurodevelopment and brain imaging were analyzed, as well as next-generation sequencing for a panel of microcephaly genes or exome sequencing. Neuropathologic and immunohistologic analyses of extremely severe microcephalic fetal brains and stage-matched controls were performed. A nonparametric test and Mann-Whitney post-test were used to compare the cortical thickness between groups.

Results: We identified 5 individuals (4 female patients, 7 years 10 months-19 years) with a particularly small brain among a series of 50, all suffering from a severe neurodevelopmental disorder with no ability to communicate verbally and, in 3 of them, no ability to walk. Genetic analysis revealed in all individuals the presence of the same homozygous variant c.2953A>G (p.R985G) in the RTTN gene (ROTATIN). The same variant was found in 2 fetuses whose neuropathologic evaluation showed a major reduction in the thickness of the ventricular zone and neuronal heterotopias. The cortical plate was reduced by 70% compared with controls, irrespective of the region considered. Immunostaining with vimentin showed a 50% loss of radial glial columns, characteristic of radial microbrain.

Discussion: Our data show that the homozygous c.2953A>G substitution in RTTN is a recurrent variant responsible for radial microbrain, the most severe form of primary microcephaly. Our combined neurologic, imaging, and histopathologic approaches provide a better understanding of the severity of this condition and its prognosis.

Trial registration information: ClinicalTrials.gov number: NCT01565005.

Abstract

Trophoblast fusion into the multinucleated syncytiotrophoblast (SCT) appears as an inescapable feature of placentation in mammals and other viviparous species. The trophoblast cells underlying the syncytium are considered a reservoir for the restoration of the aging peripheric structure. The transition from trophoblasts to SCTs has to be tightly regulated, and could be altered by genetic anomalies or environmental exposure. The resulting defective placental function could be one of the causes of the major placental diseases, such as preeclampsia (PE) and Intra-Uterine Growth Restriction (IUGR). This review attempts to take stock of the current knowledge about fusion mechanisms and their deregulations

Abstract

Background : data on preschool neurodevelopment of preterm infants according to the duration of their neonatal exposure to opioids with/without midazolam is limited. We aimed to assess neurodevelopment outcome in children aged five years, born very preterm (24–31 weeks), according to exposure to these drugs.

Methods : secondary analysis from the French prospective cohort study EPIPAGE-2 (Etude Epidémiologique sur les Petits Ages Gestationnels, 2011). Exposure to opioids with/without midazolam was classified as none, ≤7 or >7 days. Percentages were weighted to account for the study design. The primary outcome was moderate/severe neurodevelopmental disabilities (NDD). Analyses were conducted using logistic regression and adjusted for perinatal confounders.

Findings : among 3117 survivors, 1165 (35.9%) were exposed (762/1165 (68.0%) ≤7 days, 403/1165 (32.0%) >7 days). Of these 49.5% received opioids only, 41.4% opioids and midazolam, and 9.1% midazolam only. Moderate/severe NDD occurred in 17.8%, 18.9%, and 31.7% in the unexposed, exposed ≤7 days, and exposed >7 days groups, respectively. After adjustment for baseline confounders, only exposure >7 days was associated with increased rates of moderate/severe NDD (adjusted odds ratio 2.07; 95% CI 1.32–3.26). After additional adjustment for severe neonatal morbidities no significant association was found between any duration of exposure and NDD.

Interpretation : exposure to opioids with/without midazolam >7 days might be associated with a higher prevalence of moderate/severe NDD at five years in very preterm born children but severe neonatal morbidities are a major modulator of this association.

Abstract

Respiratory syncytial virus (RSV) is a leading cause of infant morbidity. France has implemented a national campaign using nirsevimab to prevent RSV-related infections in infants. This study assessed its effectiveness in preventing hospitalization due to bronchiolitis in emergency department (ED). This retrospective study was conducted among six pediatric EDs in the Greater Paris area, France, and included infants aged < 3 months with a clinical diagnosis of bronchiolitis during the 2023-2024 RSV epidemic season. The primary outcome was hospitalization after the ED visits. The association with nirsevimab immunization was assessed using a multiple logistic model adjusted for potential confounding factors, with missing data handled using random forest imputation. Secondary analyses examined the risk of admission to the pediatric intensive care unit (PICU), RSV positivity, and subgroup analyses of prematurity, neonates, and deprivation using the FDep index (area-based measure of social deprivation in France). Between October 2 and December 31, 2023, 739 infants were included in the study. A total of 531 (72%) patients had a documented nirsevimab immunization status, and 402 (54%) were hospitalized following a bronchiolitis diagnosis. Nirsevimab showed 53.5% adjusted effectiveness in reducing hospitalizations (95% CI 34.1-67.3). Sensitivity analyses of complete-case data and propensity score matching yielded similar results. Nirsevimab also resulted in 51.1% reduction in PICU admissions (95% CI 10.7-74.3) and 79.6% reduction in RSV positivity (95% CI 68.0-87.1). The protective effect of immunization was consistent for preterm infants, neonates, and deprived groups, though the results were not statistically significant in these smaller subgroups.

Conclusions: Immunization with nirsevimab reduced hospitalization following an ED visit for bronchiolitis among infants aged < 3 months.

What is known: • Nirsevimab reduces the risk of bronchiolitis-related hospitalizations in clinical trials. • Real-world data from the immunization campaign in France remain limited.

What is new: • Nirsevimab showed 53.5% (95% CI 34.1-67.3) adjusted effectiveness in reducing hospitalizations for all-cause bronchiolitis in infants aged < 3 months in emergency departments. • Analyses included social deprivation and highlighted potential disparities in immunization access.

Keywords: Bronchiolitis; Immunization; Nirsevimab; Pediatric; RSV

Abstract

To assess the short-term safety of doxapram for treating apnea of prematurity. This is a retrospective and bicenter study. Eligible children were born before 28 weeks of gestation from January 1, 2020 to December 31, 2021. The association between doxapram treatment and gastrointestinal events was assessed with logistic regression models with adjustment for the main confounding factors: center, sex, intra-uterine growth restriction and gestational age. The main outcome measures are gastrointestinal events (necrotizing enterocolitis or feeding intolerance), the adverse effects of doxapram most frequently reported in the literature. The population consisted of 268 children; 113 (42.2%) received doxapram. As compared with children who did not receive doxapram, those who did had lower gestational age at birth (25.4 vs 26.3 weeks), lower birth weight and more evidence of greater clinical respiratory severity. Doxapram treatment was not associated with increased risk of gastrointestinal events (30.1% and 29.7% in the treated and untreated groups; odds ratio 1.3, 95% CI 0.7-2.4, p = 0.43). More children in the treated than untreated group had high blood pressure (25.7% vs 6.5%).

Conclusion: In children born before 28 weeks of gestation, doxapram treatment for apnea of prematurity was not associated with the occurrence of gastrointestinal events.

What is known: • Doxapram is a well-known second-line treatment for apnea of prematurity. It is a central nervous stimulant that can be used in refractory apnea of prematurity despite continuous positive airway pressure and optimal caffeine therapy. However, its use varies among countries and centers, probably because of suspected adverse effects. Studies suggest that this drug may have potential side effects such as digestive events (necrotizing enterocolitis).

What is new: • We present reassuring data on the digestive safety of doxapram. Use of this drug was not associated with increased rates of digestive events in preterm infants born before 28 weeks of gestation.