Publications

Abstract

Background: Children born preterm face higher risks of neurodevelopmental difficulties that, with social vulnerabilities, may impair school performance. We described and assessed determinants of receiving school support in preterm-born children in France.

Methods: We used data from the prospective population-based cohort of births before 35 weeks’ gestation in France, EPIPAGE-2, to estimate crude rates and adjusted relative risks (using multivariable, mixed-effects generalized linear models) of receiving school support at age five, by children’s neurodevelopment at five, sociodemographic characteristics, and region.

Results: Out of 3,007 children, 99% attended mainstream school at age five, of whom 9% received school support. Support was more often received by boys (11%; aRR = 1.37) than girls (6%), children born at 24-27 weeks’ gestation (21%; aRR = 2.78 compared to 32-34 weeks), and children with moderate or severe neurodevelopmental impairments (MSNDI: cerebral palsy, cognitive impairment, visual impairment or blindness, and/or hearing impairment or deafness) (39%; aRR = 17.25 compared to none). Receiving support was not associated with sociodemographic characteristics, after adjusting for covariates.

Conclusions: Neurodevelopmental impairment is a key determinant for receiving school support. However, 9% of the cohort and under 40% of children with MSNDI were receiving support, raising questions on whether unmet needs for school support exist in France.

Impact: This study provides an overview of school support received at age five by children born before 35 weeks’ gestation in France, and associated determinants Less than 10% of the total cohort and 40% of children with a moderate or severe neurodevelopmental impairment were receiving school support Cognitive and neurodevelopmental impairments were key determinants for receiving school support, but sociodemographic characteristics were not Our results raise questions about whether unmet needs for school support exist, calling for further research on the support available in schools, decision-making processes for allocating them, and the psychosocial and academic consequences of their provision on children.

Abstract

Objective: To evaluate the occurrence of multiple gestation birth and perinatal adverse outcomes in pregnancies resulting from clomiphene citrate (CC) treatment compared with nonexposed pregnancies.

Design: Nationwide cohort study in a university hospital-based research center.

Subjects: Pregnancies lasting >22 weeks of gestation, in women aged 18-43 years between 2013 and 2019, recorded in the French health data warehouse (Système National des Données de Santé).

Exposure: Pregnancies exposed to CC were assigned to a 1:5 unexposed control cohort on the basis of maternal age, calendar year of childbirth, French social deprivation index, history of hypertension, and history of diabetes. The exclusion criteria were in vitro fertilization/intracytoplasmic sperm injection treatment or gonadotropins within 12 months before pregnancy and pregnancies occurring in women with the dispensing of CC between 12 and 2 months and/or less 11 days before the beginning of the pregnancy.

Main outcome measures: Multiple gestation birth rate and perinatal outcomes.

Results: Of 3,173,013 pregnancies, 32,010 (1%) occurred in women exposed to CC, of whom 31,934 were assigned to 159,670 unexposed control pregnancies. The multiple pregnancy rate was significantly higher in CC-exposed pregnancies (5.2% vs. 1.4%; odds ratio [OR], 3.9; 95% confidence interval [CI], 3.7-4.1) such as twin pregnancies (5.1% vs. 1.4%; OR, 3.9; 95% CI, 3.7-4.1) and triple or more pregnancies (0.13% vs. 0.03%; OR, 4.3; 95% CI, 2.9-6.5) than in the unexposed control cohort. Women exposed to CC presented significantly more adverse obstetric and perinatal outcomes, including stillbirths, premature delivery threats, premature rupture of membranes, gestational diabetes, placenta previa, gravid hypertension, preeclampsia, preterm birth, small for gestational age, and cesarean section rate. After stratification on multiple pregnancy and adjustment on confounders (history of psychiatric disease, obesity, and embryo reduction during pregnancy), exposure to CC remains associated with adverse outcomes in both singleton and multiple pregnancies.

Conclusion: A fourfold risk of multiple gestation births was found in pregnancies exposed to CC, along with perinatal adverse events, even in singletons. Although it remains uncertain whether these adverse events are because of the medication itself or to the treated medical condition, these findings should provide awareness of practitioners and patients about its use. It also underscores the importance of attentively monitoring follicular growth during the treatment process to avoid multiple pregnancies.

Abstract

Importance: Progress in perinatal care has improved survival for children born very preterm (VPT), but these children remain at higher risk of cognitive impairment compared with children born at term.

Objective: To synthesize cohort studies on childhood cognitive ability following VPT birth to investigate trends over time.

Data sources: All studies from 5 previous meta-analyses of VPT birth and cognition published before 2019 were included, and PubMed, Web of Science, and PsycInfo were searched for new studies published up to June 2024.

Study selection: Studies reporting IQ scores of children (aged <18 years) born VPT (<32 weeks’ gestational age [GA] or birth weight <1500 g) with a term-born comparison group were included.

Data extraction and synthesis: Two reviewers independently selected studies, extracted data, and evaluated study quality using a modified version of the Newcastle-Ottawa Scale. Unique cohorts were identified to avoid duplicate measures from studies on the same children.

Main outcomes and measures: The standardized mean difference (SMD) of IQ scores between VPT-born and term-born children was calculated, and mixed-effects metaregression was used to investigate linear and nonlinear associations between median birth year and the SMD. The main analysis focused on cohorts with IQ measured between 4 and 7 years of age to allow comparison at similar assessment ages. Secondary analyses were conducted in all cohorts using IQ obtained at the latest assessment age.

Results: A total of 257 studies reported data from 131 cohorts of 25 746 individuals born from 1977 to 2016 (15 548 born VPT and 10 198 at term). In the 61 cohorts assessed at age 4 to 7 years (13 842 children born between 1977 and 2014 [8847 born VPT and 4995 at term]; mean [SD] GA, 28.2 [1.7] weeks for the VPT cohorts), IQ was lower for VPT-born children compared with term-born children (SMD = -0.88; 95% CI, -0.97 to -0.79). The linear model showed no association with birth year (β = -0.002; 95% CI,-0.012 to 0.008). Three types of nonlinear models were fit, with no nonlinear associations observed. Adjustment for GA and study characteristics did not change the results (β = -0.001; 95% CI, -0.013 to 0.011). Secondary analysis of 131 cohorts found a similar difference between VPT and term groups (SMD = -0.84; 95% CI, -0.90 to -0.79), with no time trend (β = 0.001; 95% CI, -0.005 to 0.007).

Conclusions and relevance: On average, children born VPT had significantly lower IQ scores than term-born children, and this deficit did not decrease in studies conducted over 4 decades.

Abstract

Objective: The objective is to investigate the prevalence of underweight and overweight and obesity (OWOB) and associated risk factors among 5-year-old children born very preterm (VPT).

Design: Multinational area-based cohort study of children born VPT.

Setting: 19 regions in 11 European countries.

Patients: Children born before 32 weeks of gestational age in 2011-2012 and followed up at 5 years of age.

Main outcome measures: Body mass index (BMI) at 5 years of age was classified into underweight and OWOB using International Obesity Task Force references, and associations with sociodemographic, perinatal and neonatal risk factors were assessed using multinomial logistic regression. Data came from medical records during the neonatal hospitalisation and parental questionnaires at 5 years of age. Models accounted for missing data and attrition by using multiple imputation by chained equations and inverse probability weighting.

Results: 27.6% of children were underweight and 10.8% were OWOB. Younger maternal age was associated with lower risks of underweight, while low maternal education, household unemployment and non-European maternal country of birth were associated with having OWOB. Fetal growth restriction, receiving postnatal steroids and bronchopulmonary dysplasia were associated with underweight, and fetal growth restriction, male sex and multiple birth were negatively associated with OWOB.

Conclusions: 38% of children born VPT had suboptimal BMI at 5 years, principally due to being underweight, with differing risk factors for underweight and OWOB. These results raise questions about underlying mechanisms and the growth trajectories and metabolic outcomes of underweight children, in light of high prevalence and association with clinical risk

Abstract

Objective: To evaluate obstetric and perinatal outcomes of pregnancies among patients with osteogenesis imperfecta using the French National Health Insurance Database.

Methods: We conducted a retrospective cohort study. Pregnancies were identified with an algorithm specifically developed for the French National Health Insurance Database to identify delivery stays using a combination of International Classification of Diseases, Tenth Revision (ICD-10) discharge codes and medical procedures. Exposure was osteogenesis imperfecta status based on the occurrence of ICD-10 code Q780 5 years before conception or during pregnancy. Outcomes included pregnancy, delivery, postpartum, and fetal complications based on hospital discharge data and reimbursements of medical procedures, medical devices, and drugs. Multivariable logistic regression analysis was performed, adjusted for multiple pregnancies per participant with generalized estimating equations.

Results: The cohort included 8,850,969 pregnancies (5,823,322 patients) between January 2012 and December 2023. In total, 408 pregnant individuals (4.6/100,000) were identified with osteogenesis imperfecta. Compared with pregnant individuals without osteogenesis imperfecta, pregnant individuals with osteogenesis imperfecta had increased risks of antepartum hemorrhage (adjusted risk ratio [RR] 1.78, 95% CI, 1.01-3.14), chorioamnionitis (adjusted RR 2.79, 95% CI, 1.17-6.64), malpresentation (adjusted RR 1.65, 95% CI, 1.19-2.30), and preterm delivery (adjusted RR 2.11, 95% CI, 1.62-2.74). Cesarean delivery rates were notably higher in pregnant individuals with osteogenesis imperfecta (adjusted RR 2.59, 95% CI, 2.34-2.88), including among nulliparous individuals (adjusted RR 2.50, 95% CI, 2.22-2.81). Osteogenesis imperfecta was associated with major congenital anomalies (adjusted RR 5.04, 95% CI, 3.97-6.39 overall; adjusted RR 1.67, 95% CI, 1.09-2.56 when osteogenesis imperfecta was excluded from the congenital anomaly definition), especially cardiac anomalies. Postpartum analysis indicated no significant increase in fracture rates compared with prepregnancy periods.

Conclusion: In this nationwide cohort study, osteogenesis imperfecta was associated with both maternal and fetal complications. These findings underscore the need for specialized, multidisciplinary management of pregnancies in patients with osteogenesis imperfecta

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.