Publications

Abstract

Background & aims: Body mass index (BMI) is used to identify high-risk groups in childhood and to target early interventions to prevent later metabolic disorders. This is a priority area for research among children born very preterm (VPT) given growing concern with their long-term risks of adverse metabolic outcomes. Two principal international BMI classifications exist for underweight, overweight and obesity (OWOB) in children (International Obesity Task Force (IOTF) and World Health Organization (WHO)), but how the choice of reference affects results of research in children born VPT is unknown. Our objective was to compare the prevalence and risk factors for underweight and OWOB using these two references among five-year-old children born VPT.

Methods: Data comes from a population-based cohort of children born VPT in 11 European countries in 2011-12 with information from medical records during the neonatal hospitalization and parental questionnaires at age five. BMI at five years of age was classified into underweight and OWOB using IOTF and WHO references (n=2,654 children). Conversion algorithms were also applied to prevalence estimates. Associations with sociodemographic, perinatal and neonatal characteristics were assessed using multinomial logistic regression with multiple imputation and inverse probability weighting to account for missing data and attrition.

Results: After applying a cutoff of -1SD to define mild underweight for WHO – since this category exists only for IOTF – the estimated prevalence of total underweight was similar between IOTF and WHO references (27.8% vs 27.0%, respectively). IOTF classified a higher proportion of children as having severe underweight (4.1% vs 1.6%). For OWOB, prevalence estimates were lower using IOTF, particularly among boys (8.6% vs 14.1%). The algorithms provided good conversion (1-2% absolute difference) of prevalence between references for underweight and obesity overall, and overweight for girls, but had a larger error for overweight in boys. Risk factors were similar for underweight and OWOB for both references, with the exception of sex and maternal country of birth (OWOB significantly associated using IOTF but not WHO references).

Conclusion: Clinicians and researchers should be aware of the difference in prevalence of suboptimal BMI when interpreting findings from studies using different classifications and IOTF should be used with caution for investigating sex differences. Given the high prevalence of mild underweight in children born VPT, the cutoff of -1SD should be used with the WHO references in studies of BMI in this population.

Keywords: Body mass index; IOTF growth charts; Overweight and obesity; Underweight; Very preterm; WHO growth charts.

Abstract

Background & aims: Body mass index (BMI) is used to identify high-risk groups in childhood and to target early interventions to prevent later metabolic disorders. This is a priority area for research among children born very preterm (VPT) given growing concern with their long-term risks of adverse metabolic outcomes. Two principal international BMI classifications exist for underweight, overweight and obesity (OWOB) in children (International Obesity Task Force (IOTF) and World Health Organization (WHO)), but how the choice of reference affects results of research in children born VPT is unknown. Our objective was to compare the prevalence and risk factors for underweight and OWOB using these two references among five-year-old children born VPT.

Methods: Data comes from a population-based cohort of children born VPT in 11 European countries in 2011-12 with information from medical records during the neonatal hospitalization and parental questionnaires at age five. BMI at five years of age was classified into underweight and OWOB using IOTF and WHO references (n=2,654 children). Conversion algorithms were also applied to prevalence estimates. Associations with sociodemographic, perinatal and neonatal characteristics were assessed using multinomial logistic regression with multiple imputation and inverse probability weighting to account for missing data and attrition.

Results: After applying a cutoff of -1SD to define mild underweight for WHO – since this category exists only for IOTF – the estimated prevalence of total underweight was similar between IOTF and WHO references (27.8% vs 27.0%, respectively). IOTF classified a higher proportion of children as having severe underweight (4.1% vs 1.6%). For OWOB, prevalence estimates were lower using IOTF, particularly among boys (8.6% vs 14.1%). The algorithms provided good conversion (1-2% absolute difference) of prevalence between references for underweight and obesity overall, and overweight for girls, but had a larger error for overweight in boys. Risk factors were similar for underweight and OWOB for both references, with the exception of sex and maternal country of birth (OWOB significantly associated using IOTF but not WHO references).

Conclusion: Clinicians and researchers should be aware of the difference in prevalence of suboptimal BMI when interpreting findings from studies using different classifications and IOTF should be used with caution for investigating sex differences. Given the high prevalence of mild underweight in children born VPT, the cutoff of -1SD should be used with the WHO references in studies of BMI in this population.

Keywords: Body mass index; IOTF growth charts; Overweight and obesity; Underweight; Very preterm; WHO growth charts.

Abstract

Background: Hypertensive disorders of pregnancy represent a major cause of maternal and fetal morbidity and mortality. Despite primary aldosteronism (PA) being the most common cause of secondary hypertension, there is limited data on pregnancy complications in patients with PA.

Methods: We conducted an international survey across 5 Hypertension Centers in Europe to gather data on maternal and neonatal complications in women diagnosed with PA from 2000 to 2022. We included 102 women aged 18 to 45 years at PA diagnosis who were pregnant either after or <1-year before the diagnosis of PA. The first eligible pregnancy for each patient was included.

Results: Overall, 56% of pregnancies were complicated, with the most frequent complications being maternal preeclampsia (36%), preterm birth (30%), low birth weight (30%), and neonatal intensive care admission (22%). Hypokalemia occurred in 31% of pregnancies. Pregnancies occurring before PA diagnosis presented a poorer blood pressure control and were associated with higher rates of overall, maternal, and fetal/neonatal complications compared with pregnancies in patients with an established PA diagnosis. Independent predictors of complications included uncontrolled blood pressure values during pregnancy (odds ratio [OR], 7.05), undiagnosed PA (OR, 4.37), North/Black African ethnicity (OR, 3.69), a higher body mass index (OR, 1.09), and treatment with a higher number of antihypertensive drugs at PA diagnosis (OR, 2.18).

Conclusions: PA is associated with a high rate of pregnancy-related complications, predominantly preeclampsia. Undiagnosed PA during gestation significantly increases the risk of adverse outcomes. Early identification and optimized hypertension control in women with PA are critical to improve maternal and fetal outcomes.

Keywords: aldosterone; blood pressure; body mass index; hypokalemia; pregnancy.

Abstract

Genome-wide Association Studies (GWAS) have played a crucial role in uncovering the genetics underlying complex human traits. Recently, there has been considerable interest in adapting GWAS-like methodologies to investigate pathogenic bacteria. Despite the variety of methods proposed, there remains a lack of clarity on how to effectively model the intricate population structures found in bacterial cohorts. In this study, we analyze the genetic architecture of whole-genome sequencing data from three distinct bacterial species, showing that the standard models used in human genetics, typically employed by existing bacterial GWAS methods, fall short when applied to organisms with highly structured genomes. Building on these findings, we introduce ChoruMM, a robust and powerful multi-component linear mixed model. This model infers components through hierarchical clustering of the bacterial genetic relatedness matrix. Extensive simulations show that our approach reduces false positives while maintaining, or even improving, detection rates compared to current pipelines. The ChoruMM package includes post-processing and visualization tools designed to address the prevalent issue of long-range correlations in bacterial genomes, enabling accurate assessment and calibration of type I error rates.

Abstract

Background and objective: Extremely preterm infants are at very high risk of neonatal death and disabilities. Their survival rate is much variable in developed countries and in France is much lower than other countries. Our objective is to evaluate the impact of an intervention to standardize the perinatal management of extremely preterm infants.

Population: Women hospitalized between 22 and 26 weeks for risk of preterm delivery with a alive fetus or a stillbirth at admission and with a delivery between 22 and 26 completed weeks.

Intervention: Our complex intervention aimed at standardizing the organization of care based on the following principles: A collective obstetric-pediatric prognostic assessment, in a non-emergency setting, with a consensus decision about the obstetric and neonatal management proposed-either active or palliative care; An interview with the parents to inform them, answer their questions, propose either active or palliative care and then ask their opinion.

Methods: A Stepped-wedge cluster-randomized trial. Perinatal networks will be randomly allocated to the intervention in 5 waves every 3 months, with a total recruitment period of 21 months (including 3-month transition periods). All perinatal networks will have a period with and without the intervention. After the allocation of clusters to the intervention period, the teams will be trained in the intervention protocol and then will undergo a 3-month transition period to learn the protocol thoroughly.

Sample size: We hypothesis hypothesized is that survival without severe morbidity will could rise from 20 to 35% after the intervention, but envisaged different scenarios with varying survival without severe morbidity in the control and intervention periods. The intraclass correlation coefficients was set to 0.07. With an average number of 60 to 70 extremely preterm infants recruited per year, a number of 20 clusters (perinatal networks) were was sufficient to provide at least 80% power in most scenarios, and 25 clusters would provide at least 80% power in all scenarios envisaged.

Setting: Twenty-five perinatal networks including 34 neonatal level-3 hospital, and 285 maternity units overall.

Outcome: Child’s survival without severe morbidity at hospital discharge.

Expected results: Improvement of the health of extremely preterm infants and, if the intervention shows that it is effective, equitable access to care according to place of birth in France.

Ethics: The protocol was approved by the Committee for Protection of Persons Involved in Biomedical Research (CPP Ile de France V PARIS), and the French Data Protection Authority (30/12/2021, N°21.03700000050-MS02).

Trial registration: The trial was registered before the beginning of the study at ClinicalTrials.gov (December 20, 2021-NCT05248477).

Keywords: Extremely preterm infants; Organization of care; Perinatal management; Perinatal network.

Abstract

Introduction: In preterm pre-labor rupture of membranes (PPROM) before 34 weeks, expectant management is preferred in the absence of infection to reduce neonatal morbidity. Outpatient management (OM) has emerged as a potential alternative to prolonged hospitalization, but selection criteria remain ill-defined. Our objective was to evaluate latency between PPROM and delivery, and obstetric and neonatal outcomes before and after the implementation of an OM protocol and its subsequent extensions.

Material and methods: We included all women with PPROM before 34 weeks admitted between January 1, 2011, and December 31, 2021. Two periods were compared: Period A (January 2011-April 2013), when all patients were hospitalized until delivery, and Period B (May 2013-December 2021), when eligible patients were offered OM. Period B was subdivided into three phases (B1-B3) reflecting progressive expansion of eligibility criteria-from stable singleton pregnancies with cephalic presentation and normal amniotic fluid (B1), to inclusion of twins and shorter stabilization periods (B2), and finally cases with oligohydramnios or non-cephalic presentations (B3). The primary outcome was latency period (days between PPROM and delivery). Secondary outcomes included obstetric and neonatal complications. Comparisons were made between Periods A and B and across OM subperiods.

Results: A total of 539 patients were included: 145 in Period A and 394 in Period B, of whom 126 (32%) received OM. Mean gestational age at PPROM was similar between periods (28.9 ± 3.1 vs. 28.9 ± 3.3 weeks; p = 0.94), as were latency (median 7 [3-17] days vs. 8 [2-21]; p = 0.66) and gestational age at delivery (30.8 ± 3.3 vs. 30.9 ± 3.8 weeks; p = 0.62). Early neonatal bacterial infection was significantly lower in Period B (24.2% vs. 34.5%; p = 0.01). OM use increased steadily from B1 to B3 without prolonging latency or worsening outcomes.

Conclusion: Following OM protocol implementation, one-third of eligible women with PPROM before 34 weeks were managed at home. Outpatient care, even with broadened eligibility, appeared safe, did not increase maternal or neonatal morbidity, and may reduce early neonatal infections without extending latency.

Keywords: home monitoring; latency period; neonatal outcomes; obstetric complications; outpatient management (OM); preterm premature rupture of membranes (PPROM)

Abstract

Objective: Early-onset neonatal sepsis due to ascending infection is a potentially preventable complication of preterm premature rupture of membranes. Our objective was to determine whether the analysis of bacteria from vaginal swab samples is predictive of the risk of early-onset neonatal sepsis in preterm premature rupture of membranes.

Study design: In a prospective 3-center observational cohort, patients with preterm premature rupture of membranes were enrolled between 22 and 36 weeks of gestation + 6 days. Vaginal swab samples at delivery were analyzed using 2 different approaches, classical bacterial cultures and shotgun metagenomic sequencing analysis. A metagenomics score was constructed combining the characterization of the vaginal microbiome and the presence of pathogens and the optimal cutoff to predict early-onset neonatal sepsis was tested on a receiver operating curve.

Results: Five hundred sixty-three preterm premature rupture of membranes cases were enrolled, with 646 live-born neonates. Preterm premature rupture of membranes occurred<32 weeks of gestation in 41.9% and deliveries were<34 weeks of gestation in 41.0%. The incidence of early-onset neonatal sepsis was 29/646 (4.5%). When considering all central and peripheral microbiological samples available for 26 neonates, the main pathogens isolated were Escherichia coli in 14 cases (53.8%), other gram-negatives in 5 (19.2%), strict anaerobes in 3 (11.5%); there was a single case (3.8%) each with Group B Streptococcus, Streptococcus anginosus, Staphylococcus aureus, and Ureaplasma urealyticum. We studied the prediction of early-onset neonatal sepsis among 272 mothers and their 310 neonates (20 early-onset neonatal sepsis, 6.4%) with both culture and metagenomic data available. A culture positive for a major or intermediate pathogen in the vaginal sample at delivery had a sensitivity of 80.0% (95% confidence interval=56.3-94.3) and a specificity of 37.9% (95% confidence interval=32.3-43.8), adjusted odds ratio of 1.6 (95% confidence interval [0.5-5.0]) to predict early-onset neonatal sepsis. The presence of E. coli was associated with an early-onset neonatal sepsis risk of 10.6% vs 4.9%, in the absence of E. coli (P=0.07). The metagenomics score was highly associated with early-onset neonatal sepsis, with an area under the receiver operating curve of 0.75 (95% confidence interval, 0.61-0.90). At the optimal cutoff value, sensitivity was 70% (95% confidence interval, 64%% to 95%), specificity was 85% (95% confidence interval, 81%% to 89%). A metagenomics score greater than 40 was associated with a significantly increased risk of early-onset neonatal sepsis with an adjusted odds ratio of 8.9 (95% confidence interval [3.5; 22.3]) in multivariate analysis adjusted for latency period and gestational age, P<0.001.

Conclusion: In preterm premature rupture of membranes, conventional microbial culture of maternal vaginal samples was associated with early-onset neonatal sepsis, but its predictive values remain insufficient to guide perinatal care. Metagenomic microbial signatures improved predictive values. This opens the perspective for a rapid point-of-care test.

Keywords: Nugent score; ascending-route infection; bacterial culture; early-onset neonatal sepsis; metagenomics; pregnancy, preterm premature rupture of membranes (PPROM); vaginal microbiota; vaginal swab sampling.

Abstract

Background: Bronchopulmonary dysplasia (BPD) is the most common morbidity of very preterm (VPT) infants born < 32 weeks’ gestation with lifelong consequences. Studies document wide variation between regions and units in BPD prevalence.

Research question: Which unit-level factors contribute to the variation in BPD prevalence among VPT infants in European neonatal units?

Study design and methods: Analyses were conducted using the prospective population-based Effective Perinatal Intensive Care in Europe (EPICE) cohort in 19 regions in 11 European countries. We compared prevalence of moderate/severe BPD among VPT infants without severe congenital anomalies in neonatal units with ≥ 40 annual VPT admissions (83 units and 5,285 infants). Unit prevalence was adjusted for individual risk factors using standardized morbidity rates. Spearman correlation and multilevel logistic regression were used to assess associations of BPD with unit-level variables: unit mortality rates, first week oxygen saturation targets, proportion of infants ventilated within the first 24 hours, unit practice of postnatal corticosteroid use for hypotension or BPD prevention, and unit volume.

Results: Unadjusted BPD prevalence ranged from 2% to 47% (median, 13%) between units and was 8% to 42% (median, 17%) after adjustment and standardization. Oxygen saturation targets, proportion of initial mechanical ventilation, and postnatal corticosteroid use partly explained the between-unit variability (proportional change of variance: 25%, 5%, and 17%, respectively), leaving 53% unexplained. Risk-adjusted in-hospital mortality (range, 8%-21%) and patient volume were not correlated with BPD prevalence.

Interpretation: Our results show that large variability in BPD prevalence exists between European units, which was only partially explained by patient characteristics. Our findings suggest that improving respiratory management for VPT infants could be beneficial for reducing BPD prevalence. The association of unit postnatal corticosteroid use practice with BPD requires further investigation.

Keywords: bronchopulmonary dysplasia; chronic lung disease; cohort study; mechanical ventilation; mortality; oxygen saturation target; postnatal steroids; practice variations; very preterm.

Abstract

Introduction: In preterm pre-labor rupture of membranes (PPROM) before 34 weeks, expectant management is preferred in the absence of infection to reduce neonatal morbidity. Outpatient management (OM) has emerged as a potential alternative to prolonged hospitalization, but selection criteria remain ill-defined. Our objective was to evaluate latency between PPROM and delivery, and obstetric and neonatal outcomes before and after the implementation of an OM protocol and its subsequent extensions.

Material and methods: We included all women with PPROM before 34 weeks admitted between January 1, 2011, and December 31, 2021. Two periods were compared: Period A (January 2011-April 2013), when all patients were hospitalized until delivery, and Period B (May 2013-December 2021), when eligible patients were offered OM. Period B was subdivided into three phases (B1-B3) reflecting progressive expansion of eligibility criteria-from stable singleton pregnancies with cephalic presentation and normal amniotic fluid (B1), to inclusion of twins and shorter stabilization periods (B2), and finally cases with oligohydramnios or non-cephalic presentations (B3). The primary outcome was latency period (days between PPROM and delivery). Secondary outcomes included obstetric and neonatal complications. Comparisons were made between Periods A and B and across OM subperiods.

Results: A total of 539 patients were included: 145 in Period A and 394 in Period B, of whom 126 (32%) received OM. Mean gestational age at PPROM was similar between periods (28.9 ± 3.1 vs. 28.9 ± 3.3 weeks; p = 0.94), as were latency (median 7 [3-17] days vs. 8 [2-21]; p = 0.66) and gestational age at delivery (30.8 ± 3.3 vs. 30.9 ± 3.8 weeks; p = 0.62). Early neonatal bacterial infection was significantly lower in Period B (24.2% vs. 34.5%; p = 0.01). OM use increased steadily from B1 to B3 without prolonging latency or worsening outcomes.

Conclusion: Following OM protocol implementation, one-third of eligible women with PPROM before 34 weeks were managed at home. Outpatient care, even with broadened eligibility, appeared safe, did not increase maternal or neonatal morbidity, and may reduce early neonatal infections without extending latency.

Keywords: home monitoring; latency period; neonatal outcomes; obstetric complications; outpatient management (OM); preterm premature rupture of membranes (PPROM).

Abstract

Objective: The Dat’AIDS score was developed to predict 5-year mortality risk in people living with HIV aged 60 and older. However, its validity in people living with HIV aged 70 years and older needed confirmation.

Methods: This was a multicentre prospective cohort study in the Dat’AIDS French cohort. We calculated the Dat’AIDS score and Veterans Aging Cohort Study (VACS) indices 1.0 and 2.0 in people living with HIV aged 70 or older, at their first medical visit between 01/06/2014 and 31/12/2017. Participants were followed until 31 December 2019 (before the COVID-19 era). Discrimination and calibration of the Dat’AIDS score were assessed using Harrell’s C-statistic and comparisons of predicted versus observed survival probabilities. The comparison of the discriminative capacity of the Dat’AIDS score with the VACS indices was performed.

Results: A total of 1330 participants (75.5% male, median age: 73.7 years, median time since HIV diagnosis: 21.7 years, median time under combination antiretroviral therapy (cART): 19.9 years, median CD4 cell count: 553 cells/μL, HIV-1 RNA ≤50 copies/mL: 88.7%) were included. Overall, 221 (16.6%) deaths were recorded during 5598 patient-years of follow-up. The Dat’AIDS score showed good discrimination (C-statistic: 0.72; 95% confidence interval [CI; 0.68-0.75]). Calibration was good except for the moderate-risk group (5% difference). The Dat’AIDS score showed better discrimination than VACS 1.0 and 2.0 with albumin, aspartate aminotransferase (AST) and alanine transaminase (ALT) normal value imputation (C-statistic: 0.72 vs. 0.69 for both) and was similar to VACS 2.0 without imputation (0.72 vs. 0.71), that could be calculated in 99.1%, 98.6% and 34.0%, respectively.

Conclusions: The Dat’AIDS score showed good discrimination and calibration in people living with HIV aged 70 years and older, providing an easy and valuable tool for clinical decision-making and research.

Keywords: DAT’AIDS; HIV infection; aged; cohort; validation study