Publications

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.

Abstract

Objective: Treatment of coronavirus disease 2019 is mostly symptomatic, but a wide range of medications are under investigation against severe acute respiratory syndrome coronavirus 2. Although pregnant women are excluded from clinical trials, they will inevitably receive therapies whenever they seem effective in nonpregnant patients and even under compassionate use.

Methods: We conducted a review of the literature on placental transfer and pregnancy safety data of drugs under current investigation for coronavirus disease 2019.

Results: Regarding remdesivir, there are no data in pregnant women. Several other candidates already have safety data in pregnant women, because they are repurposed drugs already used for their established indications. Thus, they may be used in pregnancy, although their safety in the context of coronavirus disease 2019 may differ from conventional use. These include HIV protease inhibitors such as lopinavir/ritonavir that have low placental transfer, interferon that does not cross the placental barrier, and hydroxychloroquine or chloroquine that has high placental transfer. There are also pregnancy safety and placental transfer data for colchicine, steroids, oseltamivir, azithromycin, and some monoclonal antibodies. However, some drugs are strictly prohibited in pregnancy because of known teratogenicity (thalidomide) or fetal toxicities (renin-angiotensin system blockers). Other candidates including tocilizumab, other interleukin 6 inhibitors, umifenovir, and favipiravir have insufficient data on pregnancy outcomes.

Conclusion: In life-threatening cases of coronavirus disease 2019, the potential risks of therapy to the fetus may be more than offset by the benefit of curing the mother. Although preclinical and placental transfer studies are required for a number of potential anti-severe acute respiratory syndrome coronavirus 2 drugs, several medications can already be used in pregnant women.

Comment: No abstract available.

Abstract

Malaria during pregnancy is a major cause of maternal morbidity as well as fetal and neonatal mortality. Previous studies, including our own, suggested that placental and peripheral cytokine and chemokine levels measured at delivery can be used as biomarkers for pregnancy outcomes. However, the timing of malaria infection during pregnancy matters, and these studies do not address the effect of different cytokines in peripheral blood plasma samples taken at early and midpregnancy and at delivery. Here, we aimed to investigate whether peripheral plasma cytokine levels were associated with pregnancy outcomes in a cohort of 400 Beninese pregnant women. Using a high-sensitivity cytometry-based method, we quantified the levels of interleukin-4 (IL-4), IL-5, IL-10, IL-12p70, and gamma interferon (IFN-γ) in peripheral plasma samples taken at two time points during pregnancy and at delivery in various groups of pregnant women identified with Plasmodium falciparum infection, with anemia, with preterm births, or giving birth to babies who are small for their gestational age. We found that, consistently at all time points, elevated levels of IL-10 were strongly and significantly associated with P. falciparum infection, while the levels of IFN-γ at inclusion and delivery were weakly but also significantly associated. Low levels of IL-5 at delivery were associated with a greater risk of both preterm births and small-for-gestational-age babies. The immunosuppressive effects of IL-10 likely affect the overall cytokine equilibrium during pregnancy in women harboring P. falciparum infections. Our findings highlight the peripheral signature of pregnancy outcomes and strengthen the idea of using cytokines as diagnostic or prognostic markers.

Abstract

Objective: The Society of Maternal Fetal Medicine (SMFM) and the Amniotic Fluid Embolism Foundation have recently proposed four diagnostic criteria for amniotic fluid embolism (AFE): presence of (1) sudden cardiac arrest or both respiratory and hemodynamic collapse, and (2) biological disseminated intravascular coagulopathy (DIC), and (3) absence of fever, and (4) clinical onset during labor or within 30 min of delivery. The objectives of our study were to describe the clinical presentation of women with a strong suspicion of AFE and to assess the validity of the four criteria proposed for AFE definition.

Material and methods: We performed a retrospective study including all patients with a strong suspicion of AFE who delivered between 2006 and 2018 at the Port Royal maternity unit, Paris. Strong suspicion of AFE was defined by a clinical presentation in favor of AFE associated with a biological pattern and/or autopsy result supporting AFE. The mention of AFE in files was essential to include the patients in our study. We estimated the incidence and mortality rate of AFE. Then, the presence of each of the four diagnosis criteria of the SMFM score was described, as well as the clinical and biological patterns.

Results: Among the 54 140 women who delivered during the study period, 14 had a strong suspicion of AFE (0.03 %), accounting for 25.9/100 000 deliveries (95 %CI (12.3-39.5/100,000)). All women had biological tests or autopsy supporting the diagnosis of AFE. Six of 14 patients (43 %) presented with all the four diagnostic criteria of the SMFM definition. All 14 women presented a hemodynamic collapse, but respiratory symptoms were lacking in 8 patients (57 %); 71 % fulfilled the criterion of biological DIC, and all patients had a clinical coagulopathy and a massive postpartum hemorrhage. Absence of fever was lacking in three women. In addition, all patients presented premonitory symptoms such as neurological disorders or irreversible and inaugural fetal bradycardia.

Conclusion: The four SMFM diagnostic criteria were present in less than half of the women with a strong suspicion of AFE. We propose an alternative clinical and pragmatic definition to diagnose AFE, which has to be validated in the future. Early diagnosis of AFE based solely on clinical criteria can help clinicians anticipate the severity of the situation and optimize care.

Abstract

Key points: Maternal hypertension is associated with increased rates of pregnancy pathologies, including fetal growth restriction, due at least in part to reductions in nitric oxide (NO) bioavailability and associated vascular dysfunction. Dietary nitrate supplementation, from beetroot juice (BRJ), has been shown to increase NO bioavailability and improve cardiovascular function in both preclinical and clinical studies. This study is the first to investigate effects of dietary nitrate supplementation in a pregnant animal model. Importantly, the effects of nitrate-containing BRJ were compared with both ‘placebo’ (nitrate-depleted) BRJ as well as water to control for potential nitrate-independent effects. Our data show novel, nitrate-independent effects of BRJ to lower blood pressure and improve vascular function in endothelial nitric oxide synthase knockout (eNOS^-/- ) mice. These findings suggest potential beneficial effects of BRJ supplementation in pregnancy, and emphasize the importance of accounting for nitrate-independent effects of BRJ in study design and interpretation.

Abstract: Maternal hypertension is associated with adverse pregnancy outcomes, including fetal growth restriction (FGR), due in part to reductions in nitric oxide (NO) bioavailability. We hypothesized that maternal dietary nitrate administration would increase NO bioavailability to reduce systolic blood pressure (SBP), improve vascular function and increase fetal growth in pregnant endothelial NO synthase knockout (eNOS^-/- ) mice, which exhibit hypertension, endothelial dysfunction and FGR. Pregnant wildtype (WT) and eNOS^-/- mice were supplemented with nitrate-containing beetroot juice (BRJ+) from gestational day (GD) 12.5. Control mice received an equivalent dose of nitrate-depleted BRJ (BRJ-) or normal drinking water. At GD17.5, maternal SBP was measured; at GD18.5, maternal nitrate/nitrite concentrations, uterine artery (UtA) blood flow and endothelial function were assessed, and pregnancy outcomes were determined. Plasma nitrate concentrations were increased in both WT and eNOS^-/- mice supplemented with BRJ+ (P < 0.001), whereas nitrite concentrations were increased only in eNOS^-/- mice (P < 0.001). BRJ- did not alter nitrate/nitrite concentrations. SBP was lowered and UtA endothelial function was enhanced in eNOS^-/- mice supplemented with either BRJ+ or BRJ-, indicating nitrate-independent effects of BRJ. Improvements in endothelial function in eNOS^-/- mice were abrogated in the presence of 25 mm KCl, implicating enhanced EDH signalling in BRJ- treated animals. At GD18.5, eNOS^-/- fetuses were significantly smaller than WT animals (P < 0.001), but BRJ supplementation did not affect fetal weight. BRJ may be a beneficial intervention in pregnancies associated with hypertension, endothelial dysfunction and reduced NO bioavailability. Our data showing biological effects of non-nitrate components of BRJ have implications for both interpretation of previous findings and in the design of future clinical trials.