Publications

Abstract

Objective: To assess the risk of gestational hypertension (GH) and pre-eclampsia (PE) during a second pregnancy after occurrence during a first pregnancy.

Design: Prospective cohort study.

Setting: CONCEPTION is a French nationwide cohort study that used data from the National Health Data System (SNDS) database.

Methods: We included all women who gave birth for the first time in France in 2010-2018 and who subsequently gave birth. We identified GH and PE through hospital diagnoses and the dispensing of anti-hypertensive drugs. The incidence rate ratios (IRR) of all hypertensive disorder of pregnancy (HDP) during the second pregnancy were estimated using Poisson models adjusted for confounding.

Main outcome measures: Incidence rate ratios of HDP during the second pregnancy.

Results: Of the 2 829 274 women included, 238 506 (8.4%) were diagnosed with HDP during their first pregnancy. In women with GH during their first pregnancy, 11.3% (IRR 4.5, 95% confidence interval [CI] 4.4-4.7) and 3.4% (IRR 5.0, 95% CI 4.8-5.3) developed GH and PE during their second pregnancy, respectively. In women with PE during their first pregnancy, 7.4% (IRR 2.6, 95% CI 2.5-2.7) and 14.7% (IRR 14.3, 95% CI 13.6-15.0) developed GH and PE during their second pregnancy, respectively. The more severe and earlier the PE during the first pregnancy, the stronger the likelihood of having PE during the second pregnancy. Maternal age, social deprivation, obesity, diabetes and chronic hypertension were all associated with PE recurrence.

Conclusion: These results can guide policymaking that focuses on improving counselling for women who wish to become pregnant more than once, by identifying those who would benefit more from tailored management of modifiable risk factors, and heightened surveillance during post-first pregnancies.

Abstract

Background: Many clinical trials have reported that low-dose aspirin decreases the risk of pre-eclampsia in women with prior pre-eclampsia. However, its impact in a real-world population has not been fully assessed.

Objectives: To assess the rates of low-dose aspirin initiation during pregnancy in women with a history of pre-eclampsia, and to evaluate the impact of low-dose aspirin in prevention of pre-eclampsia recurrence in a real-world population.

Study design: CONCEPTION is a French nationwide cohort study which uses data from the country’s National Health Data System database. We included all women in France who gave birth at least twice between 2010-2018, and who had pre-eclampsia during their first pregnancy. Every dispensing of low-dose aspirin (75-300 mg) between the beginning of their second pregnancy and 36 weeks of gestation (WG) was identified. We used Poisson regression models to estimate the adjusted incidence rate ratios (aIRRs) of receiving aspirin at least once during their second pregnancy. In women who had early and/or severe pre-eclampsia during their first pregnancy, we estimated the IRRs of pre-eclampsia recurrence during their second pregnancy according to the aspirin therapy.

Results: In 28,467 women who were included in the study, the aspirin initiation rate during the second pregnancy ranged from 27.8% for women in whose first pregnancy the pre-eclampsia was mild and late, to 79.9% for those women whose pre-eclampsia was severe and early. Just over half (54.3%) of those treated with aspirin-initiated treatment before 16 WG and adhered to treatment. Compared with women with mild and late pre-eclampsia, the aIRRs (95% CI) for receiving aspirin at least once during the second pregnancy were 1.94 (1.86-2.03) for women with severe and late pre-eclampsia, 2.34 (2.17-2.52) for those with early and mild pre-eclampsia, and 2.87 [2.74-3.01] for those with early and severe pre-eclampsia E. Social deprivation was associated with a lower initiation of aspirin (IRR = 0.74 [0.70-0.78]). Aspirin was not associated with a lower risk of mild and late pre-eclampsia, severe and late pre-eclampsia, or mild and early pre-eclampsia during the second pregnancy. The aIRRs for severe and early pre-eclampsia during the second pregnancy were 0.77 (0.62-0.95) for women who received prescribed aspirin at least once, 0.71 (0.5-0.89) for those who initiated aspirin therapy before 16 WG, and 0.60 (0.47-0.77) for those who adhered to aspirin treatment throughout their second pregnancy. The risk of severe and early pre-eclampsia was lower only when the prescribed mean daily dose was ≥ 100 mg/day.

Conclusion: In women with a history of pre-eclampsia, aspirin initiation during a second pregnancy and adherence to the prescribed dosage were largely insufficient, especially for women experiencing social deprivation. Aspirin initiated before 16 WG at a dose ≥ 100 mg/day was associated with a lower risk of severe and early pre-eclampsia.

Abstract

Objective: To investigate whether extrauterine growth restriction (EUGR) during the neonatal hospitalisation by sex among extremely preterm (EPT) infants is associated with cerebral palsy (CP) and cognitive and motor abilities at 5 years of age.

Study design: Population-based cohort of births <28 weeks of gestation with data from obstetric and neonatal records and parental questionnaires and clinical assessments at 5 years of age.

Setting: 11 European countries.

Patients: 957 EPT infants born in 2011-2012.

Main outcomes: EUGR at discharge from the neonatal unit was defined as (1) the difference between Z-scores at birth and discharge with <-2 SD as severe, -2 to -1 SD as moderate using Fenton’s growth charts (Fenton) and (2) average weight-gain velocity using Patel’s formula in grams (g) per kilogram per day (Patel) with <11.2 g (first quartile) as severe, 11.2-12.5 g (median) as moderate. Five-year outcomes were: a CP diagnosis, intelligence quotient (IQ) using the Wechsler Preschool and Primary Scales of Intelligence tests and motor function using the Movement Assessment Battery for Children, second edition.

Results: 40.1% and 33.9% children were classified as having moderate and severe EUGR, respectively, by Fenton and 23.8% and 26.3% by Patel. Among children without CP, those with severe EUGR had lower IQ than children without EUGR (-3.9 points, 95% Confidence Interval (CI)=-7.2 to -0.6 for Fenton and -5.0 points, 95% CI=-8.2 to -1.8 for Patel), with no interaction by sex. No significant associations were observed between motor function and CP.

Conclusions: Severe EUGR among EPT infants was associated with decreased IQ at 5 years of age.

Abstract

Background: SARS-CoV-2 can lead to several types of complications during pregnancy. Variant surges are associated with different severities of disease. Few studies have compared the clinical consequences of specific variants on obstetrical and neonatal outcomes. Our goal was to evaluate and compare disease severity in pregnant women and obstetrical or neonatal complications between variants of SARS-CoV-2 that have circulated in France over a two-year period (2020-2022).

Method: This retrospective cohort study included all pregnant women with a confirmed SARS-CoV-2 infection (positive naso-pharyngeal RT-PCR test) from March 12, 2020 to January 31, 2022, in three tertiary maternal referral obstetric units in the Paris metropolitan area, France. We collected clinical and laboratory data for mothers and newborns from patients’ medical records. Variant identification was either available following sequencing or extrapolated from epidemiological data.

Results: There were 234/501 (47%) Wild Type (WT), 127/501 (25%) Alpha, 98/501 (20%) Delta, and 42/501 (8%) Omicron. No significative difference was found regarding two composite adverse outcomes. There were significantly more hospitalizations for severe pneumopathy in Delta variant than WT, Alpha and Omicron respectively (63% vs 26%, 35% and 6%, p<0.001), more frequent oxygen administration (23% vs 12%, 10% and 5%, p = 0,001) and more symptomatic patients at the time of testing with Delta and WT (75% and 71%) versus Alpha and Omicron variants (55% and 66% respectively, p<0.01). Stillbirth tended to be associated with variants (p = 0.06): WT 1/231 (<1%) vs 4/126 (3%), 3/94 (3%), and 1/35 (3%) in Alpha, Delta and Omicron cases respectively. No other difference was found.

Conclusion: Although the Delta variant was associated with more severe disease in pregnant women, we found no difference regarding neonatal and obstetrical outcomes. Neonatal and obstetrical specific severity may be due to mechanisms other than maternal ventilatory and general infection

Abstract

Aim: To assess the predictive validity of parent-reported gross motor impairment (GMI) at age 2 years to detect significant movement difficulties at age 5 years in children born extremely preterm.

Method: Data were from 556 children (270 males, 286 females) born at less than 28 weeks’ gestation in 2011 to 2012 in 10 European countries. Parent report of moderate/severe GMI was defined as walking unsteadily or unable to walk unassisted at 2 years corrected age. Examiners assessed significant movement difficulties (score ≤ 5th centile on the Movement Assessment Battery for Children, Second Edition) and diagnoses of cerebral palsy (CP) were collected by parent report at 5 years chronological age.

Results: At 2 years, 66 (11.9%) children had moderate/severe GMI. At 5 years, 212 (38.1%) had significant movement difficulties. Parent reports of GMI at age 2 years accurately classified CP at age 5 years in 91.0% to 93.2% of children. Classification of moderate/severe GMI at age 2 years had high specificity (96.2%; 95% confidence interval 93.6-98.0) and positive predictive value (80.3%; 68.7-89.1) for significant movement difficulties at age 5 years. However, 74.5% of children with significant movement difficulties at 5 years were not identified with moderate/severe GMI at age 2 years, resulting in low sensitivity (25.1%; 19.4-31.5).

Interpretation: This questionnaire may be used to identify children born extremely preterm who at age 2 years have a diagnosis of CP or movement difficulties that are likely to have a significant impact on their functional outcomes at age 5 years.

ABSTRACT

Bacterial colonization in the gut plays a pivotal role in neonatal necrotizing enterocolitis (NEC) development, but the relationship between bacteria and NEC remains unclear. In this study, we aimed to elucidate whether bacterial butyrate end-fermentation metabolites participate in the development of NEC lesions and confirm the enteropathogenicity of Clostridium butyricum and Clostridium neonatale in NEC. First, we produced C.butyricum and C.neonatale strains impaired in butyrate production by genetically inactivating the hbd gene encoding β-hydroxybutyryl-CoA dehydrogenase that produces end-fermentation metabolites. Second, we evaluated the enteropathogenicty of the hbd-knockout strains in a gnotobiotic quail model of NEC. The analyses showed that animals harboring these strains had significantly fewer and less intense intestinal lesions than those harboring the respective wild-type strains. In the absence of specific biological markers of NEC, the data provide original and new mechanistic insights into the disease pathophysiology, a necessary step for developing potential novel therapies.

Abstract

In this study, we attempted to find genetic variants affecting gene expression (eQTL = expression Quantitative Trait Loci) in the human placenta in normal and pathological situations. The analysis of gene expression in placental diseases (Pre-eclampsia and Intra-Uterine Growth Restriction) is hindered by the fact that diseased placental tissue samples are generally taken at earlier gestations compared to control samples. The difference in gestational age is considered a major confounding factor in the transcriptome regulation of the placenta. To alleviate this significant problem, we propose here a novel approach to pinpoint disease-specific cis-eQTLs. By statistical correction for gestational age at sampling as well as other confounding/surrogate variables systematically searched and identified, we found 43 e-genes for which proximal SNPs influence expression level. Then, we performed the analysis again, removing the disease status from the covariates, and we identified 54 e-genes, 16 of which are identified de novo and, thus, possibly related to placental disease. We found a highly significant overlap with previous studies for the list of 43 e-genes, validating our methodology and findings. Among the 16 disease-specific e-genes, several are intrinsic to trophoblast biology and, therefore, constitute novel targets of interest to better characterize placental pathology and its varied clinical consequences. The approach that we used may also be applied to the study of other human diseases where confounding factors have hampered a better understanding of the pathology.

Abstract

Background: Cerebral malaria (CM) is a neuropathology which remains one of the deadliest forms of malaria among African children. The kinetics of the pathophysiological mechanisms leading to neuroinflammation and the death or survival of patients during CM are still poorly understood. The increasing production of cytokines, chemokines and other actors of the inflammatory and oxidative response by various local actors in response to neuroinflammation plays a major role during CM, participating in both the amplification of the neuroinflammation phenomenon and its resolution. In this study, we aimed to identify risk factors for CM death among specific variables of inflammatory and oxidative responses to improve our understanding of CM pathogenesis.

Methods: Children presenting with CM (n = 70) due to P. falciparum infection were included in southern Benin and divided according to the clinical outcome into 50 children who survived and 20 who died. Clinical examination was complemented by fundoscopic examination and extensive blood biochemical analysis associated with molecular diagnosis by multiplex PCR targeting 14 pathogens in the patients’ cerebrospinal fluid to rule out coinfections. Luminex technology and enzyme immunoassay kits were used to measure 17 plasma and 7 urinary biomarker levels, respectively. Data were analysed by univariate analysis using the nonparametric Mann‒Whitney U test and Pearson’s Chi2 test. Adjusted and multivariate analyses were conducted separately for plasma and urinary biomarkers to identify CM mortality risk factors.

Results: Univariate analysis revealed higher plasma levels of tumour necrosis factor (TNF), interleukin-1beta (IL-1β), IL-10, IL-8, C-X-C motif chemokine ligand 9 (CXCL9), granzyme B, and angiopoietin-2 and lower urinary levels of prostanglandine E2 metabolite (PGEM) in children who died compared to those who survived CM (Mann-Whitney U-test, P-values between 0.03 and < 0.0001). The multivariate logistic analysis highlighted elevated plasma levels of IL-8 as the main risk factor for death during CM (adjusted odd ratio = 14.2, P-value = 0.002). Values obtained during follow-up at D3 and D30 revealed immune factors associated with disease resolution, including plasma CXCL5, C-C motif chemokine ligand 17 (CCL17), CCL22, and urinary 15-F2t-isoprostane.

Conclusions: The main risk factor of death during CM was thus elevated plasma levels of IL-8 at inclusion. Follow-up of patients until D30 revealed marker profiles of disease aggravation and resolution for markers implicated in neutrophil activation, endothelium activation and damage, inflammatory and oxidative response. These results provide important insight into our understanding of CM pathogenesis and clinical outcome and may have important therapeutic implications.

Abstract

Early treatment of neonatal diabetes with sulfonylureas has been proven to produce marked improvements of neurodevelopment, beside the demonstrated efficacy on glycemic control. Several barriers still prevent an early treatment in preterm babies including the limited availability of suitable galenic form of glibenclamide. We adopted oral glibenclamide suspension (Amglidia) for the early treatment of neonatal diabetes due to an homozygous variant of KCNJ11 gene c.10C>T [p.Arg4Cys] in an extremely preterm infant born at 26 + 2 weeks’ of gestational age. After ~6 weeks of insulin treatment with a low glucose intake (4.5 g/kg/day), the infant was switched to Amglidia 6 mg/ml diluted in maternal milk, via nasogastric tube (0.2 mg/kg/day) progressively reduced to 0.01 mg/kg/day (after ~3 months). While on glibenclamide, the patient exhibited a mean daily growth of 11 g/kg/day. The treatment was suspended at month 6 of birth (weight 4.9 kg [5th-10th centile], M3 of c.a.) for normalization of glucose profile. During the treatment, the patient exhibited a stable glucose profile within the range of 4-8 mmol/L in the absence of hypo or hyperglycemic episodes with 2-3 blood glucose tests per day. The patient was diagnosed with retinopathy of prematurity Stade II in Zone II without plus disease at 32 weeks, with progressive regression and complete retinal vascularization at 6 months of birth. Amglidia could be regarded as the specific treatment for neonatal diabetes even in preterm babies due to its beneficial effect on the metabolic and neurodevelopmental side.

Abstract

Background: Worldwide, Escherichia coli is the leading cause of neonatal Gram-negative bacterial meningitis, but full understanding of the pathogenesis of this disease is not yet achieved. Moreover, to date, no vaccine is available against bacterial neonatal meningitis.

Methods: Here, we used Transposon Sequencing of saturated banks of mutants (TnSeq) to evaluate E. coli K1 genetic fitness in murine neonatal meningitis. We identified E. coli K1 genes encoding for factors important for systemic dissemination and brain infection, and focused on products with a likely outer-membrane or extra-cellular localization, as these are potential vaccine candidates. We used in vitro and in vivo models to study the efficacy of active and passive immunization.

Results: We selected for further study the conserved surface polysaccharide Poly-β-(1-6)-N-Acetyl Glucosamine (PNAG), as a strong candidate for vaccine development. We found that PNAG was a virulence factor in our animal model. We showed that both passive and active immunization successfully prevented and/or treated meningitis caused by E. coli K1 in neonatal mice. We found an excellent opsonophagocytic killing activity of the antibodies to PNAG and in vitro these antibodies were also able to decrease binding, invasion and crossing of E. coli K1 through two blood brain barrier cell lines. Finally, to reinforce the potential of PNAG as a vaccine candidate in bacterial neonatal meningitis, we demonstrated that Group B Streptococcus, the main cause of neonatal meningitis in developed countries, also produced PNAG and that antibodies to PNAG could protect in vitro and in vivo against this major neonatal pathogen.

Interpretation: Altogether, these results indicate the utility of a high-throughput DNA sequencing method to identify potential immunotherapy targets for a pathogen, including in this study a potential broad-spectrum target for prevention of neonatal bacterial infections.