Publications

Abstract

Background: Malaria in pregnancy (MiP) contributes significantly to infant mortality rates in Sub-Saharan Africa and has consequences on survivors, such as pre-term birth and low birth weight. However, its impact on long-term neurocognitive development in children remains unknown.

Methods: Our prospective cohort included pregnant women and their live-born singletons from the Malaria in Pregnancy Preventive Alternative Drugs clinical trial. MiP was assessed using microscopy and real-time quantitative polymerase chain-reactions (qPCR). Neurocognitive development in children was assessed using the Mullen Scales of Early Learning and the Kaufman Assessment Battery for Children 2 nd edition (KABC-II) at one and six years of age, respectively.

Results: Of 493 pregnant women, 196 (40%) were infected with malaria at least once; 121 (31%) with placental malaria diagnosed by qPCR. Multiple linear regression beta coefficients showed that impaired gross motor scores were associated with MiP at least once [-2.55 Confidence Interval (CI) (-5.15, 0.05)], placental malaria by qPCR [-4.95 CI (-7.65, -2.24)], and high parasite density at delivery [-1.92 CI (-3.86, 0.02)] after adjustment. Malaria and high parasite density at the 2 nd ANV were associated with lower KABC-II Non-Verbal Index scores at six years [-2.57 CI (-4.86, -0.28)] and [-1.91 CI (-3.51, -0.32)], respectively.

Conclusions: This prospective cohort study provides evidence that MiP, particularly late-term, could have important negative consequences on child development at one and six years of age. Mechanisms behind this association must be further investigated and diagnostic methods in low-income countries should be strengthened to provide adequate treatment.

Abstract

Background: To inform the on-going debate about the use of universal prescriptive versus national intrauterine growth charts, we compared perinatal mortality for small and large-for-gestational-age (SGA/LGA) infants according to international and national charts in Europe.

Methods: We classified singleton births from 33 to 42 weeks of gestation in 2010 and 2014 from 15 countries (N = 1,475,457) as SGA (birthweight <10th percentile) and LGA (>90th percentile) using the international Intergrowth-21st newborn standards and national charts based on the customised charts methodology. We computed sex-adjusted odds ratios (aOR) for stillbirth, neonatal and extended perinatal mortality by this classification using multilevel models.

Findings: SGA and LGA prevalence using national charts were near 10% in all countries, but varied according to international charts with a north to south gradient (3.0% to 10.1% and 24.9% to 8.0%, respectively). Compared with appropriate for gestational age (AGA) infants by both charts, risk of perinatal mortality was increased for SGA by both charts (aOR[95% confidence interval (CI)]=6.1 [5.6–6.7]) and infants reclassified by international charts from SGA to AGA (2.7 [2.3–3.1]), but decreased for those reclassified from AGA to LGA (0.6 [0.4–0.7]). Results were similar for stillbirth and neonatal death.

Interpretation: Using international instead of national charts in Europe could lead to growth restricted infants being reclassified as having normal growth, while infants with low risks of mortality could be reclassified as having excessive growth.

Abstract

Objectives: To compare mortality, morbidity and neurodevelopment by mode of delivery (MOD) for very preterm births with low prelabour risk of caesarean section (CS).

Methods: The study was a population-based prospective cohort study in 19 regions in 11 European countries. Multivariable mixed effects models and weighted propensity score models were used to estimate adjusted odds ratios (aOR) by observed MOD and the unit’s policy regarding MOD. Population: Singleton vertex-presenting live births at 24 + 0 to 31 + 6 weeks of gestation without serious congenital anomalies, preeclampsia, HELLP or eclampsia, antenatal detection of growth restriction and prelabour CS for fetal or maternal indications.

Results: Main outcome measures: A composite of in-hospital mortality and intraventricular haemorrhage (grade III/IV) or periventricular leukomalacia. Secondary outcomes were components of the primary outcome, 5 min Apgar score <7 and moderate to severe neurodevelopmental impairment at two years of corrected age. The rate of CS was 29.6% but varied greatly between countries (8.0-52.6%). MOD was not associated with the primary outcome (aOR for CS 0.99; 95% confidence interval [CI] 0.65-1.50) when comparing units with a systematic policy of CS or no policy of MOD to units with a policy of vaginal delivery (aOR 0.88; 95% CI 0.59-1.32). No association was observed for two-year neurodevelopment impairment for CS (aOR 1.15; 95% CI 0.66-2.01) or unit policies (aOR 1.04; 95% CI 0.63-1.70).

Conclusions: Among singleton vertex-presenting live births without medical complications requiring a CS at 24 + 0 to 31 + 6 weeks of gestation, CS was not associated with improved neonatal or long-term outcomes.

Abstract

Background & aims: Extra-uterine growth restriction (EUGR) is common among very preterm (VPT) infants and has been associated with impaired neurodevelopment. Some research suggests that adverse effects of EUGR may be more severe in boys. We investigated EUGR and neurodevelopment at 2 years of corrected age (CA) by sex in a VPT birth cohort.

Methods: Data come from a population-based cohort of children born <32 weeks’ gestation from 11 European countries and followed up at 2 years CA. Postnatal growth during the neonatal hospitalization was measured with: (1) birthweight and discharge-weight Z-score differences using Fenton charts (2) weight-gain velocity using Patel’s model. Published cut-offs were used to define EUGR as none, moderate or severe. Neurodevelopmental impairment was assessed using a parent-report questionnaire, with standardized questions/instruments on motor function, vision, hearing and non-verbal cognition. We estimated relative risks (RR) adjusting for maternal and neonatal characteristics overall and by sex.

Results: Among 4197 infants, the prevalence of moderate to severe impairment at 2 years CA was 17.7%. Severe EUGR was associated with neurodevelopmental impairment in the overall sample and the interaction with sex was significant. For boys, adjusted RR were 1.57 (95% Confidence Intervals (CI): 1.18-2.09) for Fenton’s delta Z-score and 1.50 (95% CI: 1.12-2.01) for Patel’s weight-gain velocity, while for girls they were 0.97 (0.76-1.22) and 1.12 (0.90-1.40) respectively.

Conclusion: EUGR was associated with poor neurodevelopment at 2 years among VPT boys but not girls. Understanding why boys are more susceptible to the effects of poor growth is needed to develop appropriate healthcare strategies.

Abstract

This review aims at better understanding the genetics of endometriosis. Endometriosis is a frequent feminine disease, affecting up to 10% of women, and characterized by pain and infertility. In the most accepted hypothesis, endometriosis is caused by the implantation of uterine tissue at ectopic abdominal places, originating from retrograde menses. Despite the obvious genetic complexity of the disease, analysis of sibs has allowed heritability estimation of endometriosis at ~50%. From 2010, large Genome Wide Association Studies (GWAS), aimed at identifying the genes and loci underlying this genetic determinism. Some of these loci were confirmed in other populations and replication studies, some new loci were also found through meta-analyses using pooled samples. For two loci on chromosomes 1 (near CCD42) and chromosome 9 (near CDKN2A), functional explanations of the SNP (Single Nucleotide Polymorphism) effects have been more thoroughly studied. While a handful of chromosome regions and genes have clearly been identified and statistically demonstrated as at-risk for the disease, only a small part of the heritability is explained (missing heritability). Some attempts of exome sequencing started to identify additional genes from families or populations, but are still scarce. The solution may reside inside a combined effort: increasing the size of the GWAS designs, better categorize the clinical forms of the disease before analyzing genome-wide polymorphisms, and generalizing exome sequencing ventures. We try here to provide a vision of what we have and what we should obtain to completely elucidate the genetics of this complex disease.

Abstract

Aim: According to experimental studies, cardiopulmonary distress decreases after closure of patent ductus arteriosus. However, early closure of the ductus using ibuprofen or indomethacin has failed to increase survival without serious morbidity. We review relevant data aiming to define optimal early management strategies that promote early closure of ductus arteriosus without serious adverse effects.

Methods: Literature in English was searched selectively focusing on the potential of using acetaminophen for early closure of the ductus.

Results: Prophylactic ibuprofen or indomethacin intended to close the ductus, predisposes infants to ischaemia, bleeding and immune dysfunction. Acetaminophen appears to have a similar efficacy as indomethacin or ibuprofen, and all three dose-dependently constrict the ductus. Ibuprofen and indomethacin cause non-specific inhibition of prostaglandin synthesis, while acetaminophen predominantly inhibits prostaglandin E synthesis. Owing to low CYP450 activity in infancy, acetaminophen toxicity has been rarely evident. However, increasing the dosage increases the oxidative stress. We review prophylactic treatments that may increase the safety and efficacy of acetaminophen. These include vitamin A, cysteine and glutamine, and low-dose corticosteroid supplementation.

Conclusion: The current challenge is to define a safe perinatal management practice that promotes cardiorespiratory adaptation in immature infants, particularly the seamless closure of the ductus before significant cardiopulmonary distress develops.

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.