Publications

Abstract

Background: Little attention has been devoted to the role of the immunoregulatory HLA-E/-F/-G genes in malaria. We evaluated the entire HLA-E/-F/-G variability in Beninese children highly exposed to Plasmodium falciparum (P.f.) malaria.

Methods: 154 unrelated children were followed-up for six months and evaluated for the presence and number of malaria episodes. HLA-E/-F/-G genes were genotyped using massively parallel sequencing. Anti P.f. antibodies were evaluated using ELISA.

Results: Children carrying the G allele at HLA-F (-1499,rs183540921) showed increased P.f. asymptomatic/symptomatic ratio, suggesting that these children experienced more asymptomatic P.f. episodes than symptomatic one. Children carrying HLA-G-UTR-03 haplotype exhibited increased risk for symptomatic P.f. episodes and showed lower IgG2 response against P.f. GLURP-R2 when compared to the non-carriers. No associations were observed for the HLA-E gene.

Conclusion: HLA-F associations may be related to the differential expression profiles of the encoded immunomodulatory molecules, and the regulatory sites at the HLA-G 3’UTR may be associated to posttranscriptional regulation of HLA-G and to host humoral response against P.f.

Abstract

Background: Little attention has been devoted to the role of the immunoregulatory HLA-E/-F/-G genes in malaria. We evaluated the entire HLA-E/-F/-G variability in Beninese children highly exposed to Plasmodium falciparum (P.f.) malaria.

Methods: 154 unrelated children were followed-up for six months and evaluated for the presence and number of malaria episodes. HLA-E/-F/-G genes were genotyped using massively parallel sequencing. Anti P.f. antibodies were evaluated using ELISA.

Results: Children carrying the G allele at HLA-F (-1499,rs183540921) showed increased P.f. asymptomatic/symptomatic ratio, suggesting that these children experienced more asymptomatic P.f. episodes than symptomatic one. Children carrying HLA-G-UTR-03 haplotype exhibited increased risk for symptomatic P.f. episodes and showed lower IgG2 response against P.f. GLURP-R2 when compared to the non-carriers. No associations were observed for the HLA-E gene.

Conclusion: HLA-F associations may be related to the differential expression profiles of the encoded immunomodulatory molecules, and the regulatory sites at the HLA-G 3’UTR may be associated to posttranscriptional regulation of HLA-G and to host humoral response against P.f.

Abstract

Background: An estimated 30% of women in Sub-Saharan Africa suffer from soil-transmitted helminth infection during pregnancy (SHIP), which has been shown to increase risk of pre-term birth, low birth weight, and maternal anemia. A previous study in Benin found that SHIP was associated with impaired cognitive and gross motor development scores in 635 one-year-old children. The objective of the present study was to follow children prospectively to investigate whether the association between SHIP and child neurocognitive and behavioral development persisted at age six.

Principal findings: Our prospective child cohort included 487 live-born singletons of pregnant women enrolled in the Malaria in Pregnancy Preventive Alternative Drugs clinical trial in Allada, Benin. SHIP was assessed at three antenatal visits (ANVs) through collection and testing of stool samples. Neurocognitive and behavioral development was assessed in six-year-old children by trained investigators using the Kaufman Assessment Battery for Children 2nd edition and the parent-reported Strengths and Difficulties Questionnaire (SDQ). Multiple linear regression models generated coefficients and 95% confidence intervals and potential mediating factors were tested. Prevalence of SHIP was 13% at the 1st ANV, 9% at the 2nd ANV, and 1% at delivery. SHIP was not associated with low neurocognitive scores in children at six years. Higher SDQ internalizing scores, indicating increased emotional impairments in children, were associated with helminth infection at the 2nd ANV/delivery 1.07 (95% CI 0.15, 2.00) and at least once during pregnancy 0.79 (95% CI 0.12, 1.46) in adjusted models. Mediation analysis did not reveal significant indirect effects of several mediators on this association.

Conclusions: Our study shows that while SHIP is not associated with impaired long-term neurocognitive development, infections may have significant negative impacts on emotional development in six-year-old children. SHIP remains a critical public health issue, and adequate prevention and treatment protocols should be enforced in low- and middle-income countries.

Abstract

Physiological oxygen tension rises dramatically in the placenta between 8 and 14 weeks of gestation. Abnormalities in this period can lead to gestational diseases, whose underlying mechanisms remain unclear. We explored the changes at mRNA level by comparing the transcriptomes of human placentas at 8-10 gestational weeks and 12-14 gestational weeks. A total of 20 samples were collected and divided equally into four groups based on sex and age. Cytotrophoblasts were isolated and sequenced using RNAseq. Key genes were identified using two different methods: DESeq2 and weighted gene co-expression network analysis (WGCNA). We also constructed a local database of known targets of hypoxia-inducible factor (HIF) subunits, alpha and beta, to investigate expression patterns likely linked with changes in oxygen. Patterns of gene enrichment in and among the four groups were analyzed based on annotations of gene ontology (GO) and KEGG pathways. We characterized the similarities and differences between the enrichment patterns revealed by the two methods and the two conditions (age and sex), as well as those associated with HIF targets. Our results provide a broad perspective of the processes that are active in cytotrophoblasts during the rise in physiological oxygen, which should benefit efforts to discover possible drug-targeted genes or pathways in the human placenta.

Abstract

Physiological oxygen tension rises dramatically in the placenta between 8 and 14 weeks of gestation. Abnormalities in this period can lead to gestational diseases, whose underlying mechanisms remain unclear. We explored the changes at mRNA level by comparing the transcriptomes of human placentas at 8-10 gestational weeks and 12-14 gestational weeks. A total of 20 samples were collected and divided equally into four groups based on sex and age. Cytotrophoblasts were isolated and sequenced using RNAseq. Key genes were identified using two different methods: DESeq2 and weighted gene co-expression network analysis (WGCNA). We also constructed a local database of known targets of hypoxia-inducible factor (HIF) subunits, alpha and beta, to investigate expression patterns likely linked with changes in oxygen. Patterns of gene enrichment in and among the four groups were analyzed based on annotations of gene ontology (GO) and KEGG pathways. We characterized the similarities and differences between the enrichment patterns revealed by the two methods and the two conditions (age and sex), as well as those associated with HIF targets. Our results provide a broad perspective of the processes that are active in cytotrophoblasts during the rise in physiological oxygen, which should benefit efforts to discover possible drug-targeted genes or pathways in the human placenta.

Abstract

To promote breast feeding and breast pumping is essential for the most vulnerable infants even if the current coronavirus disease 2019 (COVID-19) pandemic sanitary crisis imposes more stringent hygienic measures. As recommended by the Centers for Disease Control and Prevention, World Health Organization, and Milk Bank Association, « after each pumping session, all pump part that come into contact with breast milk should be appropriately disinfected. » The present study proposed different methods than can be used and focus on the safety analysis of chlorine solution (CS) in terms of residual hypochlorous acid (HCA) and total trihalomethanes (THM). We also performed an efficacy testing of the CS approach to decontaminate the devices used to collect the milk (breast pumps and bottles). The bacteriologic results of 1,982 breast pump milk samples collected in three different settings showed a major decrease of the microbial contamination using either sterile device or decontamination with CS compared to a simple soap washing. The main messages from our study are to propose a guideline for the safe use of CS and to define situations when breast pump decontamination might be necessary: vulnerable babies for which sterile device is recommended; special circumstances, for example the current COVID-19 pandemic; special situations, for example women living in precarious conditions; or women pumping their milk at work but that would have low or no access to boiled water. Overall, cold decontamination reduced losses of milk for bacteriological reasons in human milk banks and may also be interesting to prevent horizontal contamination by virus like COVID-19.

Abstract

Introduction: Gestational age at delivery seems to be a risk factor of recurrence of preeclampsia. The objective of this study was to analyze adverse pregnancy outcomes and recurrence of preeclampsia during the subsequent pregnancy in women with a history of pre-eclampsia delivered before 26 weeks of gestation.

Material and method: We performed a retrospective study in two French tertiary care hospitals between 2000 and 2018. Patients with a history of pre-eclampsia delivered before 26 weeks of gestation were analyzed. Information on the immediate subsequent pregnancy was collected. Adverse composite outcome was defined as recurrent preeclampsia, HELLP syndrome, placental abruption, fetal growth restriction <3rd percentile or <10^e percentile with Doppler abnormalities, maternal death and fetal death.

Results: Among the 107 patients who met the criteria, 48 were analyzed for a subsequent pregnancy. Seventeen women (35.4 %) developed an adverse composite outcome, occurring for 15 women (31.2 %) before 34 weeks. Ten women (20.8 %) developed a recurrent preeclampsia occurring for 5 women (10.4 %) before 34 weeks. We related 3 HELLP syndromes, 1 placental abruption, 9 fetal growth restrictions, 3 fetal deaths and no maternal death. Compared to baseline normotensive women, chronic hypertension was significantly associated with an increased risk of adverse composite outcome (19.3 vs 58.8 %, p-value 0.014).

Conclusion: In our population, preeclampsia with delivery before 26 weeks is associated with 35.4 % of adverse composite outcomes and 20.8 % of recurrent preeclampsia during the immediate subsequent pregnancy. These results justify the importance of an ongoing monitoring of these patients during subsequent pregnancy.

Abstract 

Health consequences of tobacco exposure during pregnancy and childhood.In France, about 15% of fetuses are exposed to maternal smoking during pregnancy and about 30% of children are exposed to second-hand tobacco smoke. Furthermore, 20 to 25% of young adults are active smokers. These high rates underline the persistent need for preventive actions against tobacco exposure from pregnancy through adulthood.Tobacco exposure leads to numerous deleterious consequences on physical and mental health. During pregnancy, the main adverse effects are increased risks of congenital anomalies, in utero death, preterm delivery and low birthweight for gestational age. Children exposed to tobacco before or after birth have increased risks of sudden infant death syndrome, respiratory infections and recurrent otitis media.Adolescents and adults have similar tobacco-related complications.

Abstract

Group B Streptococcus (GBS) is the major cause of human neonatal infections. A single clone, designated CC17-GBS, accounts for more than 80% of meningitis cases, the most severe form of the infection. However, the events allowing blood-borne GBS to penetrate the brain remain largely elusive. In this study, we identified the host transmembrane receptors α5β1 and αvβ3 integrins as the ligands of Srr2, a major CC17-GBS-specific adhesin. Two motifs located in the binding region of Srr2 were responsible for the interaction between CC17-GBS and these integrins. We demonstrated in a blood-brain-barrier cellular model that both integrins contributed to the adhesion and internalization of CC17-GBS. Strikingly, both integrins were overexpressed during the postnatal period in the brain vessels of the blood-brain barrier and blood-cerebrospinal fluid barrier and contributed to juvenile susceptibility to CC17 meningitis. Finally, blocking these integrins decreased the ability of CC17-GBS to cross into the CNS of juvenile mice in an in vivo model of meningitis. Our study demonstrated that CC17-GBS exploits integrins in order to cross the brain vessels, leading to meningitis. Importantly, it provides host molecular insights into neonate’s susceptibility to CC17-GBS meningitis, thereby opening new perspectives for therapeutic and prevention strategies of GBS-elicited meningitis.

Abstract

Background: The pathogenesis of late-onset sepsis (LOS) in preterm infants is poorly understood and knowledge about risk factors, especially prenatal risk factors, is limited. This study aimed to assess the association between the cause of preterm birth and LOS in very preterm infants.

Methods: 2052 very preterm singletons from a national population-based cohort study alive at 72 h of life were included. Survival without LOS was compared by cause of preterm birth using survival analysis and Cox regression models.

Results: 437 (20.1%) had at least one episode of LOS. The frequency of LOS varied by cause of preterm birth: 17.1% for infants born after preterm labor, 17.9% after preterm premature rupture of membranes, 20.3% after a placental abruption, 20.3% after isolated hypertensive disorders, 27.5% after hypertensive disorders with fetal growth restriction (FGR), and 29.4% after isolated FGR. In multivariate analysis, when compared to infants born after preterm labor, the risk remained higher for infants born after hypertensive disorders (hazard ratio HR = 1.7, 95% CI = 1.2-2.5), hypertensive disorders with FGR (HR = 2.6, 95% CI = 1.9-3.6) and isolated FGR (HR = 2.9, 95% CI = 1.9-4.4).

Conclusion: Very preterm infants born after hypertensive disorders or born after FGR had an increased risk of LOS compared to those born after preterm labor.

Impact: Late-onset sepsis risk differs according to the cause of preterm birth. Compared with those born after preterm labor, infants born very preterm because of hypertensive disorders of pregnancy and/or fetal growth restriction display an increased risk for late-onset sepsis. Antenatal factors, in particular the full spectrum of causes leading to preterm birth, should be taken into consideration to better prevent and manage neonatal infectious morbidity and inform the parents.