Publications

Key Features

• Etude Epidémiologique sur les Petits Ages Gestationnels-2 (EPIPAGE-2) is a population-based birth cohort of extremely, very and moderately preterm infants, aiming at estimating short- and long-term outcomes and their association with individual characteristics and unit practices.
• Preterm births (terminations of pregnancy, stillbirths and live births) from 22þ 0 to 34þ 6 weeks’ gestation, and occurring in all maternity units of 25/26 regions in France in 2011, were eligible. A total of 7804 newborns were included at baseline (participation rate 93%), and 4312 were eligible for follow-up.
• From 2011 to 2017, three follow-up steps have been performed: at 1-year corrected age (parental selfadministered questionnaire, participation 90%) and 2-year corrected age (parental self-administered questionnaire, 88%, medical questionnaire, 86%). At
• 5.5 years, 3032 children were still followed; the evaluation consisted of a parental questionnaire (77%), a standardized medical examination (68%) and a neuropsychological assessment (67%).
• Detailed information was collected on maternal sociodemographic characteristics, living conditions, health and pregnancy management and complications. Regarding the child, the main domains assessed were health, health care use, nutrition and growth, gross and fine motor skills, cognitive functions, language, behaviour, quality of life and school attendance. Additional data on policies and practices of maternity and neonatal units were also collected.
• Proposals for collaborations and secondary analyses are welcomed. Data access procedures can be found on the EPIPAGE-2 website [https://epipage2.inserm.fr/index.php/en/related-research/access-to-epipage-2-data].

Abstract

Research question: What is the prevalence of embryo abnormal early cleavage (ACL) identified by time lapse and factors related to patients and treatment that explain ACL occurrence?

Design: A single-centre, retrospective cohort study. Data were collected on all IVF cycles for which embryos were observed in the EmbryoScope® between December 2015 and August 2017. Only diploid zygotes cleaved on day 2 were included. The study included 318 cycles (250 couples and 1343 embryos). Embryo videos were retrospectively analysed for ACL. The prevalence of each type of ACL was recorded. The influence of clinical factors (whether they were intrinsic to patients or specific to IVF treatment) on ACL occurrence was analysed in multivariate multilevel mixed-effect logistic regression analysis.

Results: A high prevalence of ACL was observed: 37.6% (505/1343) of embryos presented at least one ACL, 22.8% (306/1343) a trichotomous mitosis, 25.8% (347/1343) a rapid cleavage, 6.7% (90/1343) a cell fusion and two or more ACL (16.1%). Part of the variation (12-25%) in ACL occurrence could be explained by embryo origin. Trichotomous mitosis and two or more ACL phenotypes were less likely to occur in women with endometriosis or tubal pathology and tubal pathology alone, respectively. No factor related to IVF cycles was found to be statistically associated with ACL occurrence.

Conclusions: Our findings emphasize the importance of considering embryo origin when interpreting studies focusing on embryo characteristics and factors that could affect their quality. The present study is limited by a small sample size of known embryo implantations and monocentric criterion.

Abstract

Rationale: Intrauterine growth restriction (IUGR) increases the risk of bronchopulmonary dysplasia (BPD), one of the major complications of prematurity. Antenatal low-protein diet (LPD) exposure in rats induces IUGR and mimics BPD-related alveolarization disorders. Proliferator-activated receptor (PPARg) plays a key role in normal lung development and was found deregulated following LPD exposure.

Objectives: Investigate the effects of nebulized curcumin, a natural PPARg agonist, to prevent IUGR-related abnormal lung development.

Methods: We studied rat pups antenatally exposed to an LPD or control diet (CTL) and treated with nebulized curcumin (50 mg/kg) or vehicle from postnatal (P) days 1 to 5. The primary readouts were lung morphometric analyses at P21. Immunohistochemistry (P21) and microarrays (P6 and P11) were compared within animals exposed to LPD versus controls, with and without curcumin treatment.

Results: Quantitative morphometric analyses revealed that LPD induced abnormal alveolarization as evidenced by a significant increase in Mean Linear Intercept (MLI) observed in P21 LPD-exposed animals. Early curcumin treatment prevented this effect and two-way ANOVA analysis demonstrated significant interaction between diet and curcumin both for MLI (F_(1,39)=12.67,p=0.001) and Radial Alveolar Count at P21 (F_(1,40)= 6.065, p=0.0182). Immunohistochemistry for FABP4, a major regulator of PPARg pathway showed a decreased FABP4⁺ alveolar cell density in LPD-exposed animals treated by curcumin. Transcriptomic analysis showed that early curcumin significantly prevented the activation of pro-fibrotic pathways observed at P11 in LPD-exposed animals.

Conclusion: Nebulized curcumin appears to be a promising strategy to prevent alveolarization disorders in IUGR rat pups, targeting pathways involved in lung development.

Abstract

Objective: To assess whether children with symptomatic CHD at birth (cyanosis and/or heart failure) are at greater risk of adverse neurodevelopmental outcomes at 8 years of age.

Study design: From a prospective population-based cohort study of newborns with CHD (EPICARD), we included 473 children with available neurodevelopmental assessments at 8 years of age. We grouped the CHD based on symptoms at birth and need for early neonatal intervention. Ventricular septal defects that closed spontaneously within the first year of life were considered the control group. Neurodevelopmental outcomes were assessed using K-ABC II for IQ (Mean100±15), and the NEPSY-II for detailed assessment of specific neurocognitive domains (Mean 10±3). Multivariable regression analysis was used to compare the outcomes across the CHD groups after considering potentially confounding variables.

Results: Compared with the control group, children with cyanotic CHD without heart failure had lower scores for IQ, -7.2 [95%CI: -13.4; -1.2]. Children with non-cyanotic CHD with heart failure had lower scores in the specific domains of language -1.5 [95%CI: -2.2; -0.7], and memory and learning -1.3 [95%CI: -2.4; -0.3]. Those with both cyanotic CHD and heart failure had lower scores for IQ -7.6 [95%CI: -13.5; – 1.8], as well as, the specific domains of language, memory and learning; -2.0 [95%CI: -2.9; -1.0], -1.1 [95%CI: -2.3; -0.1], respectively.

Conclusion: Children with symptomatic CHD at birth are at greater risk of adverse neurodevelopmental outcomes at 8 years of age, with the highest risk for those who were born with both cyanosis and heart failure.

Abstract

Background: Loss to follow-up is a major challenge for very preterm (VPT) cohorts; attrition is associated with social disadvantage and parents with impaired children may participate less in research. We investigated the impact of loss to follow-up on the estimated prevalence of neurodevelopmental impairment in a VPT cohort using different methodological approaches.

Methods: This study includes births < 32 weeks of gestational age (GA) from 4 regions in the UK and Portugal participating in a European birth cohort (N = 1737 survivors). Data on maternal characteristics, pregnancy complications, neonatal outcomes and neighborhood deprivation were collected at baseline. Neurodevelopment was assessed at 2 years of corrected age (CA) using standardized parent-report measures. We applied (1) multiple imputation (MI) and (2) inverse probability weighting (IPW) to estimate the impact of non-response on the prevalence of moderate to severe neurodevelopmental impairment and assessed violations of the missing at random (MAR) assumption using the delta method.

Results: 54.2% of children were followed-up. Follow-up was less likely when mothers were younger, multiparous, foreign-born, did not breastfeed and came from deprived areas. The prevalence of neurodevelopmental impairment was 18.4% (95% confidence interval (CI):15.9-21.1) and increased to 20.4% (95%CI: 17.3-23.4) and 20.0% (95%CI:16.9-23.1) for MI and IPW models, respectively. Simulating strong violations of MAR (children with impairments being 50% less likely to be followed-up) raised estimates to 23.6 (95%CI:20.1-27.1) CONCLUSIONS: In a VPT cohort with high loss to follow-up, correcting for attrition yielded modest increased estimates of neurodevelopmental impairment at 2 years CA; estimates were relatively robust to violations of the MAR assumption.

Abstract

Objective: The aim of this study was to evaluate the cumulative live birth rate in women undergoing in-vitro fertilization/intracytoplasmic-sperm-injection (IVF/ICSI) according to the type of chronic viral infection [HIV, hepatitis-B virus (HBV) and hepatitis-C virus (HCV)].

Design: A cohort study.

Setting: A tertiary-care university hospital.

Participants: Women with a chronic viral illness HIV, HBV or HCV- were followed until four IVF/ICSI cycles had been completed, until delivery or until discontinuation of the treatment before the completion of four cycles.

Main outcome measures: The primary outcome was the cumulative live birth rate after up to four IVF/ICSI cycles.

Results: A total of 235 women were allocated to the HIV-infected group (n = 101), the HBV-infected group (n = 114) and the HCV-infected group (n = 20). The cumulative live birth rate after four cycles was significantly lower in the HIV-infected women than in those with HBV [39.1%, 95% confidence interval (95% CI): 17.7-60.9 versus 52.8%, 95% CI: 41.6-65.5, respectively; P = 0.004]. Regarding the obstetrical outcomes, the mean birth weight was lower in the HIV-infected women than in those with HBV or HCV. Multivariate analysis indicated that the age, the anti-Müllerian hormone and the number of cycles performed were significantly associated with the chances of a live birth.

Conclusion: HIV-infected women had lower cumulative live birth rate than women with chronic hepatitis, and this was due to less favourable ovarian reserve parameters. These findings underscore the need to better inform practitioners and patients regarding fertility issues and the importance of early fertility assessment. However, larger studies are necessary to gain more in-depth knowledge of the direct impact of HIV on live birth rates.

Abstract

Background and Objectives: Congenital heart defects (CHD) and growth restriction at birth are two major causes of childhood and adult morbidity and mortality. The aim of this study was to assess the overall risk of growth restriction at birth, as measured by its imperfect proxy small (< 10th percentile) for gestational age (SGA), for newborns with CHD. 

Methods: Using data from a population-based cohort of children born with CHD, we assessed the risk of growth restriction at birth using SGA and severe SGA (3rd percentile). To compare the odds of SGA and severe SGA across five specific major CHD, we used ordinal logistic regression using isolated, minor (non-operated) ventricular septal defect (VSD) as the control group. 

Results: The overall proportion of SGA for « isolated » CHD (i.e., those not associated with other anomalies) was 13% (95% CI, 12-15%), which is 30% higher than what would be expected in the general population (i.e., 10%). The risk of severe SGA was 5% (95% CI, 4-6%) as compared with the expected 3% in the general population. There were substantial differences in the risk of overall SGA and more so severe SGA across the different CHD. The highest risk of SGA occurred for Tetralogy of Fallot (adjusted OR 2.7, 95% CI, 1.3-5.8) and operated VSD (adjusted OR 2.1, 95% CI, 1.1-3.8) as compared with the control group of minor (non-operated) VSD. 

Conclusion: The overall risks of both SGA and severe SGA were higher in isolated CHD than what would be expected in the general population with substantial differences across the subtypes of CHD. These results may provide a clue for understanding the underlying mechanisms of the relation between alterations in fetal circulation associated with different types of CHD and their effects on fetal growth.

Abstract

Introduction: After discussion with the parents, periviable infants can receive either active treatment or palliative care. The rate of active treatment in France is lower than in other developed countries, as is the survival rate of infants in this gestational age range. This study’s main objective was to assess the effect of a standardized perinatal management protocol (EXPRIM) on the neonatal outcome of children born before 27 weeks of gestation.

Methods: A before-and-after study was conducted in the two level-3 hospitals of the Risks and Pregnancy DHU to compare two 16-month periods. The EXPRIM protocol was based on routine administration of prenatal corticosteroid therapy and a scheduled combined obstetric-pediatric group prenatal prognostic evaluation, not based solely on gestational age. The study included all births between 22 weeks and 26 weeks+6 days of gestation, except in utero deaths diagnosed at admission and medical terminations of pregnancy for fetal malformation, both excluded. The principal endpoint was survival without severe neonatal morbidity.

Results: The study included 267 women: 116 (128 newborns) in period 1 and 151 (172 newborns) in period 2. The median gestational age at admission to the maternity unit was 2.5 days younger in period 2, and the number of women admitted at 22-23 weeks doubled in period 2 (59 vs 29, respectively). Overall, the rates of live births, NICU transfer, and survival without severe morbidity were similar during the two periods. More infants were liveborn between 22 and 24 weeks in period 2 (66 vs 43). Of all newborns transferred to the NICU, 26 (29%) survived without severe morbidity in period 1 and 46 (39%) in period 2. After multivariate analysis, survival without severe morbidity did not differ significantly.

Conclusion: Implementation of the EXPRIM protocol led to active treatment of more mothers and their children at the border of viability, and increased the number of children who survived without severe morbidity even if, overall, there was no statistically significant difference in percentage.

Abstract

Importance: Birth before 32 weeks’ gestation (very preterm [VPT]) and birth weight below 1500 g (very low birth weight [VLBW]) have been associated with lower cognitive performance in childhood. However, there are few investigations of the association of neonatal morbidities and maternal educational levels with the adult cognitive performance of individuals born VPT or VLBW (VPT/VLBW).

Objective: To assess differences in adult IQ between VPT/VLBW and term-born individuals and to examine the association of adult IQ with cohort factors, neonatal morbidities, and maternal educational level among VPT/VLBW participants.

Data sources: Systematic review of published data from PubMed and meta-analysis of individual participant data (IPD) of cohorts from 2 consortia (Research on European Children and Adults Born Preterm [RECAP] and Adults Born Preterm International Collaboration [APIC]).

Study selection: The meta-analysis included prospective longitudinal cohort studies that assessed the full-scale IQ of adults born VPT or VLBW and respective control groups comprising term-born adults.

Data extraction and synthesis: The study followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline for analyses of individual participant data and identified 8 studies that provided data from 2135 adults (1068 VPT/VLBW and 1067 term-born participants) born between 1978 and 1995. Meta-analyses of IPD were performed using a 1-stage approach, treating VPT birth or VLBW and cohort as random effects.

Main outcomes and measures: Full-scale IQ scores were converted to z scores within each cohort using the combined SD of VPT/VLBW participants and a control group of term-born participants, with scores centered on the mean of the control group.

Results: A total of 426 records were identified and screened. After exclusions, 13 studies were included in the aggregate meta-analysis. The IPD meta-analysis included 8 of the 9 RECAP and APIC cohorts with adult IQ data. The mean (SD) age among the 8 IPD cohorts was 24.6 (4.3) years, and 1163 participants (54.5%) were women. In unadjusted analyses, VPT/VLBW participants had mean adult IQ scores that were 0.78 SD (95% CI, -0.90 to -0.66 SD) lower than term-born participants, equivalent to a difference of 12 IQ points. Among VPT/VLBW participants, lower gestational age (score difference per week of gestation, 0.11; 95% CI, 0.07-0.14), lower birth weight z scores (score difference per 1.0 SD, 0.21; 95% CI, 0.14-0.28), the presence of neonatal bronchopulmonary dysplasia (score difference, -0.16; 95% CI, -0.30 to -0.02) or any grade of intraventricular hemorrhage (score difference, -0.19; 95% CI, -0.33 to -0.05), and lower maternal educational level (score difference, 0.26; 95% CI, 0.17-0.35) were all significantly associated with lower IQ scores in adulthood.

Conclusions and relevance: In this IPD meta-analysis, lower gestational age, lower weight for gestational age, neonatal morbidities, and lower maternal educational levels were all important risk factors associated with lower IQ among young adults born VPT or VLBW.

Abstract

Two major obstetric diseases, preeclampsia (PE), a pregnancy-induced endothelial dysfunction leading to hypertension and proteinuria, and intra-uterine growth-restriction (IUGR), a failure of the fetus to acquire its normal growth, are generally triggered by placental dysfunction. Many studies have evaluated gene expression deregulations in these diseases, but none has tackled systematically the role of alternative splicing. In the present study, we show that alternative splicing is an essential feature of placental diseases, affecting 1060 and 1409 genes in PE vs controls and IUGR vs controls, respectively, many of those involved in placental function. While in IUGR placentas, alternative splicing affects genes specifically related to pregnancy, in preeclamptic placentas, it impacts a mix of genes related to pregnancy and brain diseases. Also, alternative splicing variations can be detected at the individual level as sharp splicing differences between different placentas. We correlate these variations with genetic variants to define splicing Quantitative Trait Loci (sQTL) in the subset of the 48 genes the most strongly alternatively spliced in placental diseases. We show that alternative splicing is at least partly piloted by genetic variants located either in cis (52 QTL identified) or in trans (52 QTL identified). In particular, we found four chromosomal regions that impact the splicing of genes in the placenta. The present work provides a new vision of placental gene expression regulation that warrants further studies.