Publications

Assessing the risk of early unplanned rehospitalisation in preterm babies: EPIPAGE 2 study – PubMed

Abstract

Background: Gaining a better understanding of the probability, timing and prediction of rehospitalisation amongst preterm babies could help improve outcomes. There is limited research addressing these topics amongst extremely and very preterm babies. In this context, unplanned rehospitalisations constitute an important, potentially modifiable adverse event. We aimed to establish the probability, time-distribution and predictability of unplanned rehospitalisation within 30 days of discharge in a population of French preterm babies.

Methods: This study used data from EPIPAGE 2, a population-based prospective study of French preterm babies. Only those babies discharged home alive and whose parents responded to the one-year survey were eligible for inclusion in our study. For Kaplan-Meier analysis, the outcome was unplanned rehospitalisation censored at 30 days. For predictive modelling, the outcome was binary, recording unplanned rehospitalisation within 30 days of discharge. Predictors included routine clinical variables selected based on expert opinion.

Results: Of 3841 eligible babies, 350 (9.1, 95% CI 8.2-10.1) experienced an unplanned rehospitalisation within 30 days. The probability of rehospitalisation progressed at a consistent rate over the 30 days. There were significant differences in rehospitalisation probability by gestational age. The cross-validated performance of a ten predictor model demonstrated low discrimination and calibration. The area under the receiver operating characteristic curve was 0.62 (95% CI 0.59-0.65).

Conclusions: Unplanned rehospitalisation within 30 days of discharge was infrequent and the probability of rehospitalisation progressed at a consistent rate. Lower gestational age increased the probability of rehospitalisation. Predictive models comprised of clinically important variables had limited predictive ability.

Abstract

Objective: To determine whether the variation in neurodevelopmental disability rates between populations persists after adjustment for demographic, maternal and infant characteristics for an international very preterm (VPT) birth cohort using a standardised approach to neurodevelopmental assessment at 2 years of age.

Design: Prospective standardised cohort study.

Setting: 15 regions in 10 European countries.

Patients: VPT births: 22⁺⁰-31⁺⁶ weeks of gestation.

Data collection: Standardised data collection tools relating to pregnancy, birth and neonatal care and developmental outcomes at 2 years corrected age using a validated parent completed questionnaire.

Main outcome measures: Crude and standardised prevalence ratios calculated to compare rates of moderate to severe neurodevelopmental impairment between regions grouped by country using fixed effects models.

Results: Parent reported rates of moderate or severe neurodevelopmental impairment for the cohort were: 17.3% (ranging 10.2%-26.1% between regions grouped by country) with crude standardised prevalence ratios ranging from 0.60 to 1.53. Adjustment for population, maternal and infant factors resulted in a small reduction in the overall variation (ranging from 0.65 to 1.30).

Conclusion: There is wide variation in the rates of moderate to severe neurodevelopmental impairment for VPT cohorts across Europe, much of which persists following adjustment for known population, maternal and infant factors. Further work is needed to investigate whether other factors including quality of care and evidence-based practice have an effect on neurodevelopmental outcomes for these children.

Nephrol Dial Transplant. 2019 Nov 1;34(11):1819-1826. doi: 10.1093/ndt/gfy328.

Abstract

Preeclampsia is a hypertensive disorder of pregnancy and the clinical manifestation of severe endothelial dysfunction associated with maternal and foetal morbidity and mortality. The primum movens of the disease is the defect of invasion of the uterine arteries by foetal syncytiotrophoblasts, which causes a maladaptive placental response to chronic hypoxia and the secretion of the soluble form of type 1 vascular growth endothelial factor receptor, also called soluble fms-like tyrosine kinase 1 (sFlt-1), the major player in the pathophysiology of the disease. Among its different effects, sFlt-1 induces abnormal sensitivity of the maternal vessels to the vasoconstrictor angiotensin II. This leads to the hypertensive phenotype, recently shown to be abrogated by the administration of sildenafil citrate, which can potentiate the vasodilatory mediator nitrite oxide. This review focuses on the mechanisms of maternal endothelial dysfunction in preeclampsia and discusses the therapeutic window of sildenafil use in the context of preeclampsia, based on the results from preclinical studies and clinical trials. Safety issues recently reported in neonates have considerably narrowed this window.

Clin Infect Dis. 2019 Oct 30;69(10):1740-1748. doi: 10.1093/cid/ciz033.

BACKGROUND:

In infants, the mode of acquisition of CC17 group B Streptococcus (GBS), the hypervirulent clone responsible for late-onset disease (LOD), remains elusive.

METHODS:

In a prospective multicenter study in France, we evaluated GBS colonization in mother-baby pairs with 2 months of follow-up between 2012 and 2015. Criteria included positivity for GBS colonization at antenatal screening or at delivery. Maternal vaginal samples and infant oral cavity and stool samples were analyzed at delivery, 21 ± 7 days (D21), and 60 ± 7 days (D60) post-delivery.

RESULTS:

A total of 890 mother-baby pairs were analyzed. GBS colonized 7%, 21%, and 23% of the infants at birth, D21, and D60, respectively, of which 10%, 11%, and 13% were identified as CC17 GBS. Concordance between maternal and infant GBS type was 96%. At D21, the main risk factors for infant colonization by GBS were simultaneous maternal colonization of the vagina (odds ratio [OR], 4.50; 95% confidence interval [CI], 1.69-15.61) and breast milk (OR, 7.93; 95% CI, 3.81-17.14). Importantly, 38% (95% CI, 23%-56%) of infants colonized by CC17 GBS appeared colonized for the first time at D60 vs 18% (95% CI, 14%-24%; P < .049) of infants colonized by non-CC17 GBS. Multivariate analysis showed a higher risk for de novo infant colonization by CC17 at D60 than by other GBS (OR, 2.45; 95% CI, 1.02-5.88).

CONCLUSIONS:

The high incidence of CC17 GBS in LOD is likely due to an enhanced post-delivery mother-to-infant transmission.

Emerg Infect Dis. 2019 Oct;25(10):1851-1860. doi: 10.3201/eid2510.181177.

Abstract

Pregnant women constitute a promising sentinel group for continuous monitoring of malaria transmission. To identify antibody signatures of recent Plasmodium falciparum exposure during pregnancy, we dissected IgG responses against VAR2CSA, the parasite antigen that mediates placental sequestration. We used a multiplex peptide-based suspension array in 2,354 samples from pregnant women from Mozambique, Benin, Kenya, Gabon, Tanzania, and Spain. Two VAR2CSA peptides of limited polymorphism were immunogenic and targeted by IgG responses readily boosted during infection and with estimated half-lives of <2 years. Seroprevalence against these peptides reflected declines and rebounds of transmission in southern Mozambique during 2004-2012, reduced exposure associated with use of preventive measures during pregnancy, and local clusters of transmission that were missed by detection of P. falciparum infections. These data suggest that VAR2CSA serology can provide a useful adjunct for the fine-scale estimation of the malaria burden among pregnant women over time and space.

Editorial: No abstract available

Pregnancy Hypertens.2019Oct;18:82-87. doi: 10.1016/j.preghy.2019.09.015. Epub 2019 Sep 29

Objectives

Angiogenic factors may be involved in lung development. To evaluate the relations between maternal and cordblood angiogenic factors (sflt-1, placental growth factor [plgf], soluble endogline [seng], transforming growthfactor β [TGF-beta]) and their association with moderate and severe broncho-pulmonary dysplasia (BPD) invery preterm growth-restricted infants.

Study design

Prospective mono-centric cohort study. Twenty-four mother-child dyads featuring antepartumpreeclampsia,intra-uterine growth restriction (IUGR) and birth before 30 weeks’ gestation were included. This ensured a 80%power to test whether sflt-1 maternal levels would be twice as high in cases of BPD as in the absence of BPD.

Main outcome measures

Four pro/anti-angiogenic factors from two pathways (sflt-1, plgf and seng, TGF-beta) were measured inmaternal serum before delivery (at the time of hospitalization or the day of birth) and in neonates’ cord blood.Neonatal outcome was moderate to severe BPD, defined as oxygen requirement for at least 28 days and persistent need for oxygen or ventilatory support at 36 weeks’ postmenstrual age.

Results

Sflt-1 levels were positively correlated in maternal serum and cord blood (rs = 0.83, p < .001) but levels of plgfand TGF-beta and its receptor seng were not. Among all the factors studied in cord and maternal blood, nonewas associated with BPD.

Conclusions

In IUGR preterm babies born before 30 weeks’ gestation from pre-eclamptic mothers, serum sflt-1, plgf andseng, TGF-β levels were not correlated with BPD. The increased BPD risk in preterm neonates born from pre-eclamptic mothers cannot be related to high sflt-1 levels.

JPediatr.2019 Oct;213:22-29.e4. doi: 10.1016/j.jpeds.2019.06.001. Epub 2019 Jul 4

Objectives

To investigate the relation between neonatal intensive care unit (NICU) volume and survival, and neuromotorand sensory disabilities at 2 years in very preterm infants.

Study design

The EPIPAGE-2 (Etude Epidémiologique sur les Petits Âges Gestationnels-2) national prospective population-based cohort study was used to include 2447 babies born alive in 66 level III hospitals between 24 and 30completed weeks of gestation in 2011. The outcome was survival without disabilities (levels 2-5 of the GrossMotor Function Classification System for cerebral palsy with or without unilateral or bilateral blindness ordeafness). Units were grouped in quartiles according to volume, defined as the annual admissions of verypreterm babies. Multivariate logistic regression analyses with population average models were used.

Results

Survival at discharge was lower in hospitals with lower volumes of neonatal activity (aOR 0.55, 95% CI 0.33-0.91). Survival without neuromotor and sensory disabilities at 2 years increased with hospital volume, from 75% to 80.7% in the highest volume units. After adjustment for gestational age, small for gestational age, sex, maternal age, infertility treatment, multiple pregnancy, principal cause of prematurity, parental socioeconomic status, and mother’s country of birth, survival without neuromotor or sensory disabilities was significantly lower in hospitals with a lower volume of neonatal activity (aOR 0.60, 95% CI 0.38-0.95) than in the highest quartile hospitals.

Conclusion

These results suggest that lower neonatal intensive care unit volume is associated with lower survival without an increase in disabilities at 2years. These results could be useful to generate improvements of perinatal regionalization.

Sci Rep. 2019 Sep 27;9(1):13962. doi: 10.1038/s41598-019-50417-4. PMID: 31562365; PMCID: PMC6764989.

Abstract

First-trimester placenta (<10 gestational weeks (GW)) develops in a low oxygen environment (≈2%). Early oxygen exposure can cause oxidative damage leading to pregnancy disorders. The aim of this work was to determine the major sources of placental superoxide during early pregnancy – more specifically before 10 GW – and to study redox adaptation to increased oxygen pressure after 12 GW. Our results show that NADPH oxidase (Nox) is the main source of superoxide in first-trimester chorionic villi. Its activity is higher before 10 GW and concomitant with the location on the syncytiotrophoblast apical pole of p47phox, the Nox organizer subunit. After the increase in pO₂ pressure (12-14 GW), the activities of the antioxidant enzymes SOD1, catalase and GPX1 are increased. The redox-sensitive MAPK pathways show increased phosphorylated-p38 expression, but no variation in the phosphorylation of stress-activated protein kinase/c-Jun NH2-terminal kinase (SAPK/JNK) during first trimester, suggesting a physiological redox adaptation, whilst ERK1/2 phosphorylation is higher after 12 GW. Nox is the major superoxide source in early pregnancy (<10 GW). Increased superoxide production at 7-9 GW is associated with p38 MAPK pathway activation, suggesting that it is involved in physiological placental function and healthy early development of the placenta, through MAPK pathways.

Clin Infect Dis. 2019 Sep 27;69(8):1385-1393. doi: 10.1093/cid/ciy1073.

BACKGROUND:

In sub-Saharan Africa, malaria in the first half of pregnancy is harmful for both the mother and her fetus. However, malaria in the first trimester of pregnancy, when women are usually not protected against malaria, has been little investigated. For the first time, we assessed the effects of malaria in the first trimester on maternal and birth outcomes using a preconceptional study design.

METHODS:

From June 2014 to March 2017, 1214 women of reproductive age were recruited and followed monthly until 411 became pregnant. The pregnant women were then followed from 5-6 weeks of gestation until delivery. Path analysis was used to assess the direct effect (ie, not mediated by malaria in the second or third trimester) of malaria in the first trimester on maternal anemia and poor birth outcomes. The cumulative effect of infections during pregnancy on the same outcomes was also evaluated.

RESULTS:

The prevalence of malaria infections in the first trimester was 21.8%. Malaria in the first trimester was significantly associated with maternal anemia in the third trimester (adjusted odds ratio 2.25, 95% confidence interval 1.11-4.55). While we did not find evidence of any direct effect of first trimester malaria infections on birth outcomes, their association with infections later in pregnancy tended to increase the risk of low birth weights.

CONCLUSIONS:

Malaria infections in the first trimester were highly prevalent and have deleterious effects on maternal anemia. They highlight the need for additional preventive measures, starting in early pregnancy or even before conception.