Publications

Abstract

Background: Monitoring severe acute maternal morbidity (SAMM) appears essential for optimising care and informing health care policies, especially given changes in obstetric practices and mother profiles. International comparisons can identify areas where improvement is needed, but the comparability of indicators must be evaluated.

Objective: To assess the feasibility of monitoring SAMM using common definitions from hospital discharge databases across Europe.

Methods: We used hospital discharge data in eight countries (2 826 868 deliveries) to identify women with SAMM among all hospitalisations of women of reproductive age admitted for antenatal or delivery care. Five SAMM indicators were investigated: eclampsia, septicaemia, hysterectomy, hysterectomy associated with a diagnosis of obstetric haemorrhage, and red blood cell (RBC) transfusion associated with a diagnosis of obstetric haemorrhage. Between-country variation was described, by the ratio of the highest to lowest rates, while external validation was assessed by comparing with population-based studies on maternal morbidity.

Results: Ratios for hysterectomy and red blood cell (RBC) transfusion in the context of obstetric haemorrhage were 1:2.1 and 1:3.5, respectively. High values of hysterectomy and low values of transfusion were both consistent with high maternal mortality from haemorrhage (France, Italy, Portugal). Ratios across countries were relatively low for eclampsia (1:3.4) but very high for septicaemia (1:22.5). Compared to population-based morbidity estimates, eclampsia was over-reported in hospital databases whereas the two indicators of severe haemorrhage had good external validity.

Conclusions: In association with diagnosis codes indicating obstetric haemorrhage, hysterectomy and RBC transfusion appear to be good candidates for surveillance of maternal morbidity in Europe.

J Pediatr. 2020 Jul;222:71-78.e6. doi: 10.1016/j.jpeds.2020.03.021.

Abstract

Objective: To assess whether chorioamnionitis is associated with cerebral palsy (CP) or death at 2 years’ corrected age in infants born before 32 weeks of gestation after spontaneous birth.

Study design: EPIPAGE-2 is a national, prospective, population-based cohort study of children born preterm in France in 2011; recruitment periods varied by gestational age. This analysis includes infants born alive after preterm labor or preterm premature rupture of membranes from 24^0/7 to 31^6/7 weeks of gestation. We compared the outcomes of CP, death at 2 years’ corrected age, and « CP or death at age 2 » according to the presence of either clinical chorioamnionitis or histologic chorioamnionitis. All percentages were weighted by the duration of the recruitment period.

Results: Among 2252 infants born alive spontaneously before 32 weeks of gestation, 116 (5.2%) were exposed to clinical chorioamnionitis. Among 1470 with placental examination data available, 639 (43.5%) had histologic chorioamnionitis. In total, 346 infants died before 2 years and 1586 (83.2% of the survivors) were evaluated for CP at age 2 years. CP rates were 11.1% with and 5.0% without clinical chorioamnionitis (P = .03) and 6.1% with and 5.3% without histologic chorioamnionitis (P = .49). After adjustment for confounding factors, CP risk rose with clinical chorioamnionitis (aOR 2.13, 95% CI 1.12-4.05) but not histologic chorioamnionitis (aOR 1.21, 95% 0.75-1.93). Neither form was associated with the composite outcome « CP or death at age 2. »

Conclusions: Among infants very preterm born spontaneously, the risk of CP at a corrected age of 2 years was associated with exposure to clinical chorioamnionitis but not histologic chorioamnionitis.

Abstract

Objectives: To describe patterns of care for very preterm (VP) babies across neonatal intensive care units (NICUs) and associations with outcomes.

Design: Prospective cohort study, EPIPAGE-2.

Setting: France, 2011.

Participants: 53 (NICUs); 2135 VP neonates born at 27 to 31 weeks.

Outcome measures: Clusters of units, defined by the association of practices in five neonatal care domains – respiratory, cardiovascular, nutrition, pain management and neurodevelopmental care. Mortality at 2 years corrected age (CA) or severe/moderate neuro-motor or sensory disabilities and proportion of children with scores below threshold on the neurodevelopmental Ages and Stages Questionnaire (ASQ).

Methods: Hierarchical cluster analysis to identify clusters of units. Comparison of outcomes between clusters, after adjustment for potential cofounders.

Results: Three clusters were identified: Cluster 1 with higher proportions of neonates free of mechanical ventilation at 24 hours of life, receiving early enteral feeding, and neurodevelopmental care practices (26 units; n=1118 babies); Cluster 2 with higher levels of patent ductus arteriosus and pain screening (11 units; n=398 babies); Cluster 3 with higher use of respiratory, cardiovascular and pain treatments (16 units; n=619 babies). No difference was observed between clusters for the baseline maternal and babies’ characteristics. No differences in outcomes were observed between Clusters 1 and 3. Compared with Cluster 1, mortality at 2 years CA or severe/moderate neuro-motor or sensory disabilities was lower in Cluster 2 (adjusted OR 0.46, 95% CI 0.25 to 0.84) but with higher proportion of children with an ASQ below threshold (adjusted OR 1.49, 95% CI 1.07 to 2.08).

Conclusion: In French NICUs, care practices for VP babies were non-randomly associated. Differences between clusters were poorly explained by unit or population differences, but were associated with mortality and development at 2 years. Better understanding these variations may help to improve outcomes for VPT babies, as it is likely that some of these discrepancies are unwarranted.

Obstet Gynecol. 2020 Jun;135(6):1435-1443. doi: 10.1097/AOG.0000000000003862.

Abstract

Objective: To assess neonatal morbidity and mortality according to whether cephalic second twins were born after internal version followed by total breech extraction or after instructions to push. We hypothesized that interval version would result in shorter intertwin delivery intervals and lower cesarean delivery rates for the second twin and therefore better neonatal outcomes.

Methods: These planned analyses of the JUMODA (JUmeaux MODe d’Accouchement) cohort, a national prospective population-based study of twin deliveries, examined births of cephalic second twins after vaginal birth of the first twin at or after 32 weeks of gestation. The internal version group of second twins born in breech presentation after obstetric maneuvers was compared with the pushing group, comprising those born in cephalic presentation. The primary outcome was a composite of neonatal morbidity and mortality. Multivariate modified Poisson regression models were used to control for potential confounders.

Results: Of 2,256 cephalic second twins, 487 (21.6%) were born in breech presentation after internal version and total breech extraction and 1,769 (78.4%) in cephalic presentation after pushing. Composite neonatal morbidity and mortality was not lower in the internal version (17/487 [3.5%]) compared with the pushing group (38/1,769 [2.1%]; adjusted relative risk [aRR] 1.73 [95% CI 0.98-3.05]), although median [quartile 1-quartile 3] intertwin delivery intervals were shorter (5 [4-8] vs 8 [5-12] minutes, P<.001) and the cesarean delivery rate for the second twin lower (5/487 [1.0%] vs 66/1,769 [3.7%], P=.002). Subgroup analyses showed no difference between groups at or after 37 weeks of gestation but higher composite neonatal morbidity and mortality after internal version before 37 weeks (14/215 [6.5%] vs 26/841 [3.1%]; aRR 2.18 [95% CI 1.15-4.13]). Secondary analyses according to center expertise in the overall population and stratified by gestational age yielded concordant results.

Conclusion: Although our sample size precluded a robust assessment for small differences in outcomes between groups, internal version followed by total breech extraction of cephalic second twins was not associated with better neonatal outcomes than pushing.

J Cell Mol Med Actions. 2020 Jun 9;24(13):7660-7669. doi: 10.1111/jcmm.15401. Online ahead of print.

Abstract

The transcription factor peroxisome proliferator-activated receptor gamma (PPARG) is essential for placental development, and alterations in its expression and/or activity are associated with human placental pathologies such as pre-eclampsia or IUGR. However, the molecular regulation of PPARG in cytotrophoblast differentiation and in the underlying mesenchyme remains poorly understood. Our main goal was to study the impact of mutations in the ligand-binding domain (LBD) of the PPARG gene on cytotrophoblast fusion (PPARG^E352Q ) and on fibroblast cell migration (PPARG^R262G /PPARG^L319X ). Our results showed that, compared to cells with reconstituted PPARG^WT , transfection with PPARG^E352Q led to significantly lower PPARG activity and lower restoration of trophoblast fusion. Likewise, compared to PPARG^WT fibroblasts, PPARG^R262G /PPARG^L319X fibroblasts demonstrated significantly inhibited cell migration. In conclusion, we report that single missense or nonsense mutations in the LBD of PPARG significantly inhibit cell fusion and migration processes.

Developmental Medicine & Child Neurology. 2020 Jun 18. doi: 10.1111/dmcn.14587.

Abstract

Aim

To describe maternal employment and the socio‐economic status of the household up to 8 years after the very preterm birth of a child, according to the presence and type of motor or cognitive impairment.

Method

A total of 1885 families from the French EPIPAGE cohort of children who were born very preterm between 1997 and 1998 were included. Motor and cognitive impairments were identified in children between the ages of 2 and 8 years in 770 families and were classified according to type. The 1115 families with children born very preterm without these impairments were considered the reference group.

Results

Mothers of children with severe motor or cognitive impairments were less often working at 5 years after the birth than the reference mothers (21% and 30% vs 57%; p <0.001). Those working before birth returned to work less often and those not working started to work less often after the birth than did reference mothers. At 8 years, mothers of children with severe impairments reported financial difficulties more often than mothers of children without impairments.

Interpretation

Despite a fairly protective regulatory framework in France, families of infants born very preterm with severe motor or cognitive impairments are socially underprivileged. Measures to maintain an acceptable standard of living for these families and their children are needed.

JAMA Pediatr. 2020;174(10):997-999. doi:10.1001/jamapediatrics.2020.0956

Research Letter

Survival of very preterm (VPT) infants (ie, those born at <32 weeks’ gestation) has improved markedly over recent decades, raising concerns about levels of impairment among survivors. Numerous studies have been conducted on the association between VPT birth and long-term neurodevelopment and health, and this voluminous literature is increasingly synthesized in systematic reviews with meta-analyses. This methodology is considered to provide the highest level of evidence, but its validity depends on appropriate selection of primary studies and management of heterogeneity. Heterogeneity is pervasive in the literature about VPT birth because of differences in criteria for defining preterm populations, study designs, follow-up periods, follow-up rates, and clinical assessments. Furthermore, medical practices, survival, and morbidities vary markedly across countries and hospitals and can affect long-term prognosis. This study aimed to compare the selection criteria, findings, and heterogeneity of systematic reviews with meta-analyses of cognitive outcomes after VPT birth, which are of major concern in this population and measured in most studies.

Methods

We searched for systematic reviews with meta-analyses published between January 2000 and August 2019 that were based on observational studies with cohort designs investigating general cognition (IQ) for VPT children compared with a control group. We defined search terms to identify studies (1) on preterm birth (premature OR preterm OR infant, Premature [Medical Subject Headings (MeSH)]), (2) the outcome [Developmental disabilities [MeSH] OR cognition disorders [MeSH] OR intellectual disability [MeSH] OR cognition [MeSH] OR cognit* OR intelligence OR IQ, and (3) the type of study (Meta-analysis OR meta analys* OR metaanaly* OR [systematic AND review* OR overview*] OR Review Literature as Topic [MeSH]). Two of us (M.S. and J.Z.) independently abstracted methods and results related to study selection, pooled analyses, and heterogeneity. We compiled primary studies and identified unique cohorts when several studies originated from the same cohort based on the country, birth year(s), and research group. For analyses, we used R statistical software, version 3.5.0 (The R Foundation).

Results

Five reviews were identified: 1 was published in 2012¹ and 4 were published in 2018 or 2019.^2–5 All investigated the association of birth at less than 32 weeks’ gestation with childhood IQ, although some also considered other outcomes or subgroups. Eligibility criteria varied for birth weight, assessment ages, and study period (Table). We searched MEDLINE,^1–5 Embase,^1,2 PsychInfo,^1,3–5 and Web of Science^3,4 using different search terms.

Abstract

After preterm premature rupture of membranes (PPROM), antibiotics and antenatal steroids are effective evidence-based interventions, but the use of tocolysis is controversial. We investigated whether a unit policy of tocolysis use after PPROM is associated with prolonged gestation and improved outcomes for very preterm infants in units that systematically use these other evidence-based treatments. From the prospective, observational, population-based EPICE cohort study (all very preterm births in 19 regions from 11 European countries, 2011-2012), we included 607 women with a singleton pregnancy and PPROM at 24-29 weeks’ gestation, of whom 101, 195 and 311 were respectively managed in 17, 32 and 45 units with no-use, restricted and liberal tocolysis policies for PPROM. The association between unit policies and outcomes (early-onset sepsis, survival at discharge, survival at discharge without severe morbidity and survival at two years without gross motor impairment) was investigated using three-level random-intercept logistic regression models, showing no differences in neonatal or two-year outcomes by unit policy. Moreover, there was no association between unit policies and prolongation of gestation in a multilevel survival analysis. Compared to a unit policy of no-use of tocolysis after PPROM, a liberal or restricted policy is not associated with improved obstetric, neonatal or two-year outcomes.

Abstract

Introduction: Neonatal sepsis outreaches all causes of neonatal mortality worldwide and remains a major societal burden in low and middle income countries. In addition to limited resources, endemic morbidities, such as malaria and prematurity, predispose neonates and infants to invasive infection by altering neonatal immune response to pathogens. Nevertheless, thoughtful epidemiological, diagnostic and immunological evaluation of neonatal sepsis and the impact of gestational malaria have never been performed.

Methods and analysis: A prospective longitudinal multicentre follow-up of 580 infants from birth to 3 months of age in urban and suburban Benin will be performed. At delivery, and every other week, all children will be examined and clinically evaluated for occurrence of sepsis. At delivery, cord blood systematic analysis of selected plasma and transcriptomic biomarkers (procalcitonin, interleukin (IL)-6, IL-10, IP10, CD74 and CX3CR1) associated with sepsis pathophysiology will be evaluated in all live births as well as during the follow-up, and when sepsis will be suspected. In addition, whole blood response to selected innate stimuli and extensive peripheral blood mononuclear cells phenotypic characterisation will be performed. Reference intervals specific to sub-Saharan neonates will be determined from this cohort and biomarkers performances for neonatal sepsis diagnosis and prognosis tested.

Ethics and dissemination: Ethical approval has been obtained from the Comité d’Ethique de la Recherche – Institut des Sciences Biomédicales Appliquées (CER-ISBA 85 – 5 April 2016, extended on 3 February 2017). Results will be disseminated through international presentations at scientific meetings and publications in peer-reviewed journals.

Trial registration number: ClinicalTrials.gov registration number: NCT03780712.

J Gynecol Obstet Hum Reprod (2020), https://doi.org/10.1016/j.jogoh.2020.101826.

Abstract

Objective

To describe the course over time of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in French women from the beginning of the pandemic until mid-April, the risk profile of women with respiratory complications, and short-term pregnancy outcomes.

Methods

We collected a case series of pregnant women with COVID-19 in a research network of 33 French maternity units between March 1 and April 14, 2020. All cases of SARS-CoV-2 infection confirmed by a positive result on real-time reverse transcriptase polymerase chain reaction tests of a nasal sample and/or diagnosed by a computed tomography chest scan were included and analyzed. The primary outcome measures were COVID-19 requiring oxygen (oxygen therapy or noninvasive ventilation) and critical COVID-19 (requiring invasive mechanical ventilation or extracorporeal membrane oxygenation, ECMO). Demographic data, baseline comorbidities, and pregnancy outcomes were also collected.

Results

Active cases of COVID-19 increased exponentially during March 1-31, 2020; the numbers fell during April 1-14, after lockdown was imposed on March 17. The shape of the curve of active critical COVID-19 mirrored that of all active cases. By April 14, among the 617 pregnant women with COVID-19, 93 women (15.1 %; 95 %CI 12.3-18.1) had required oxygen therapy and 35 others (5.7 %; 95 %CI 4.0-7.8) had had a critical form of COVID-19. The severity of the disease was associated with age older than 35 years and obesity, as well as preexisting diabetes, previous preeclampsia, and gestational hypertension or preeclampsia. One woman with critical COVID-19 died (0.2 %; 95 %CI 0-0.9). Among the women who gave birth, rates of preterm birth in women with non-severe, oxygen-requiring, and critical COVID-19 were 13/123 (10.6 %), 14/29 (48.3 %), and 23/29 (79.3 %) before 37 weeks and 3/123 (2.4 %), 4/29 (13.8 %), and 14/29 (48.3 %) before 32 weeks, respectively. One neonate (0.5 %; 95 %CI 0.01-2.9) in the critical group died from prematurity.

Conclusion

COVID-19 can be responsible for significant rates of severe acute, potentially deadly, respiratory distress syndromes. The most vulnerable pregnant women, those with comorbidities, may benefit particularly from prevention measures such as a lockdown.