Publications

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

The developmental origin of health and disease highlights the importance of the period of the first 1000 days (from conception to 2 years) of life. In particular, the process of gut microbiota establishment occurs within this time window. Therefore, determinants interfering with neonatal gut establishment may disrupt its physiological functions and potentially lead to negative health outcomes. Antibiotics are among perinatal determinants that can directly or indirectly affect the pattern of gut bacterial colonization, with a long-lasting impact on intestinal ecosystem functions. In this review, we will examine the impact of antibiotics on the intestinal microbiota during the perinatal period and first years of life, a key interval for development of an individual’s health capital. Further, we will discuss the role of antibiotics during short- and long-term dysbiosis and their associated health consequences.

Abstract

A bioinformatics screen for non-coding genes was performed from microarrays analyzing on the one hand trophoblast fusion in the BeWo cell model, and on the other hand, placental diseases (preeclampsia and Intra-Uterine Growth Restriction). Intersecting the deregulated genes allowed to identify two miRNA (mir193b and miR365a) and one long non-coding RNA (UCA1) that are pivotal for trophoblast fusion, and deregulated in placental diseases. We show that miR-193b is a hub for the down-regulation of 135 cell targets mainly involved in cell cycle progression and energy usage/nutrient transport. UCA1 was explored by siRNA knock-down in the BeWo cell model. We show that its down-regulation is associated with the deregulation of important trophoblast physiology genes, involved in differentiation, proliferation, oxidative stress, vacuolization, membrane repair and endocrine production. Overall, UCA1 knockdown leads to an incomplete gene expression profile modification of trophoblast cells when they are induced to fuse into syncytiotrophoblast. Then we performed the same type of analysis in cells overexpressing one of the two major isoforms of the STOX1 transcription factor, STOX1A and STOX1B (associated previously to impaired trophoblast fusion). We could show that when STOX1B is abundant, the effects of UCA1 down-regulation on forskolin response are alleviated.

Abstract

Background: Regionalisation programmes aim to ensure that very preterm infants are born in level III units (inborn) through antenatal referral or transfer. Despite widespread knowledge about better survival without disability for inborn babies, 10%-30% of women deliver outside these units (outborn).

Objective: To investigate risk factors associated with outborn deliveries and to estimate the proportion that were probably or possibly avoidable.

Methods: We used a national French population-based cohort including 2205 women who delivered between 24 and 30⁺⁶ weeks in 2011. We examined risk factors for outborn delivery related to medical complications, antenatal care, sociodemographic characteristics and living far from a level III unit using multivariable binomial regression. Avoidable outborn deliveries were defined by pregnancy risk (obstetric history, antenatal hospitalisation) and time available for transfer.

Results: 25.0% of women were initially booked in level III, 9.1% were referred, 49.8% were transferred, and 16.1% had outborn delivery. Risk factors for outborn delivery were gestational age <26 weeks (adjusted relative risk (aRR) 1.37, 95% confidence interval (CI) 1.13, 1.66), inadequate antenatal care (aRR 1.39, 95% CI 1.10, 1.81), placental abruption (aRR 1.66, 95% CI 1.27, 2.17), and increased distance to the closest level III unit ((aRR 2.79, 95% CI 2.00, 3.92) in the 4th versus 1st distance quartile). Among outborn deliveries, 16.7% were probably avoidable, and 25.6% possibly avoidable, which could increase the proportion of inborn deliveries between 85.9% and 92.9%. Avoidable outborn deliveries were mainly associated with gestational age, intrauterine growth restriction, preterm premature rupture of membranes, and haemorrhage, but not distance.

Conclusions: Our study identified some modifiable risk factors for outborn delivery; however, when regionalised care relies heavily on antenatal transfer, as it does in France, only some outborn deliveries may be prevented. Earlier referral of high-risk women will be needed to achieve full access to tertiary care.

Abstract

Background: The criteria for antiphospholipid syndrome (APS) include severe preeclampsia and/or placental insufficiency leading to preterm delivery before 34 weeks of gestation, but this APS manifestation has been rarely studied. Thus, we report a series of severe preeclampsia occurred in patients with APS.

Methods: We retrospectively analysed data of women with APS (Sydney criteria) who experienced severe preeclampsia with delivery before 34 weeks’ gestation between 2000 and 2017 at five French internal medicine departments and one Italian rheumatology unit.

Results: The 40 women had a mean age of 30.5 ± 4.6 years at their first episode of preeclampsia; 21 were nulligravid (52.5%), 12 (30%) had already been diagnosed with APS, and 21 (52.5%) had a triple-positive antiphospholipid (aPL) antibody test. Preeclampsia occurred at a median gestational age of 25.5 weeks (IQR 23-29). It was associated with HELLP in 18 cases (45%), eclampsia in 6 (15%), placental abruption in 3 (7.5%), catastrophic APS in 3 (7.5%), and foetal and neonatal death in 11 and 15 cases. Overall, 14 (35%) children survived, born at a median gestational age of 31 weeks. Among other APS criteria, 16 women (40%) experienced at least one thrombosis, 17 (42.5%) an intrauterine foetal death, and 19 (47.5%) at least one episode of HELLP during follow-up (median 5 years, IQR = 2-8). None had three or more consecutive miscarriages. Notably, 12 women (30%) had systemic lupus erythematosus.

Conclusions: Severe preeclampsia led to high mortality in the offspring. Almost half of these women experienced other APS features, but not three consecutive miscarriages.

Abstract

Rural children from Benin, west Africa were evaluated with the Mullen Scales of Early Learning (MSEL) at one year of age and then at six years with the Kaufman Assessment Battery for Children (KABC-II), the visual computerized Tests of Variables of Attention (TOVA), and the Bruininks-Oseretsky Test (BOT-2) of motor proficiency (N = 568). Although both the MSEL and KABC-II were available to the assessors in French, instructions to the mother/child were in local language of Fon. Mothers were evaluated with the Edinburgh Postpartum Depression Scale (EPDS), Caldwell HOME Scale, educational level and literacy, and a Socio-Economic Scale – also in their local language (Fon). After adjusting for maternal factors, MSEL cognitive composite was correlated with KABC-II with moderate effect sizes, but not with TOVA scores. Overall eta-squared effect for the multivariate models were moderately to strongly correlated (.07 to .37). Neurodevelopmental assessments in early childhood adapted cross-culturally are predictive of school-age neuropsychological cognitive ability.