Publications

Abstract

Data on placental transfer is lacking for the recent HIV integrase inhibitors, bictegravir and cabotegravir, although their future use in pregnancy is to be expected. The objective of this study was to determine their transplacental pharmacokinetics. Maternal-to-fetal transfer was investigated using the open-circuit ex-vivo dually perfused human cotyledon model. Cabotegravir or bictegravir was added to a maternal perfusate containing 2 g/l of human albumin and antipyrine, a marker to validate the cotyledon’s viability, and cotyledons were dually perfused for up to 90 min. For cabotegravir, in five experiments, the median (IQR 25-75) concentrations in the maternal and in the fetal compartments were, respectively, 550 ng/ml (344-788) and 48 ng/ml (37-54), with a maternal-to-fetal ratio of 10% (5-16) and a clearance index (in comparison with antipyrine transfer) of 22% (19-28). The median cotyledon accumulation index was 10% (2-21). For bictegravir, in six experiments, the median (IQR 25-75) concentrations in the maternal and in the fetal compartments were, respectively, 1650 ng/ml (1455-1960) and 126 ng/ml (112-142), with a maternal-to-fetal ratio of 7% (6-9.5) and a clearance index (in comparison with antipyrine transfer) of 21% (17-29). The median cotyledon accumulation index was 4% (3-5). Placental transfer of cabotegravir and bictegravir were low. This may not only limit the potential for fetal toxicities but also be a limit to their usefulness at the time of labor and delivery to reduce the risk of vertical HIV transmission. The safety and efficacy of these new integrase inhibitors in pregnancy require more investigation.

Abstract

In a previous monocentric study in preterm neonates (PN), we described a high Clostridioides difficile colonization rate (74%) with two uncommon non-toxigenic strains (NTCD) belonging to PCR-ribotype (RT) (CE)847 and (CE)032. To determine the extent of carriage of both NTCD in other spatio-temporal settings, strains isolated in PN stools from two multicenter cohorts were characterized by PCR-ribotyping, MLVA and MLST. We also evaluated the protective role of two NTCD from these RT against C. difficile infection in a hamster caecitis model. Animals were administered either each NTCD alone (n = 7), or followed by a 027 strain (n = 9). A control group received only the 027 strain (n = 8). Clinical activity and colonization by C. difficile in stools were monitored daily until death or sacrifice at D20. We isolated 18 RT(CE)032 (ST-83) strains and 2 RT(CE)847 (ST-26) strains among 247 PN from both cohorts. Within each RT, strains were genetically related. The survival rate was significantly increased when animals received a RT(CE)847 or (CE)032 strain before the 027 strain (4/9 deaths, p = 0.029; 1/9 death, p = 0.0004, respectively). We describe two predominant uncommon NTCD strains, in a PN population from different healthcare facilities. Both NTCD provide a potential protection against C. difficile infection.

Abstract

Background: Placental passage of drugs in twins is poorly understood, and is unknown regarding antiretrovirals (ARVs). In the event of large differences in the exposure of 2 twins to the same maternal therapy, this could have a clinical impact in terms of prevention of perinatal HIV transmission or adverse effects.

Objective: To describe the frequency of differential transplacental passage of antiretrovirals between twins.

Study design: The study was performed retrospectively, on data from women included in a multicenter perinatal HIV cohort study. All twin pairs for which the mother received antiretroviral therapy and for which drug concentrations in both of the umbilical cords after cord clamping at delivery were studied. We considered that a difference in concentrations of more than 50 % between twins was a substantial difference (ratios below 0.67 or above 1.50).

Results: We analyzed 29 twin pairs, 27 dichorionic and 2 monochorionic diamniotic. Cord blood concentrations differed between the 2 twins by more than 50 % for at least one ARV in 9 twin pairs, 8 dichorionic and 1 monochorionic. Discordant concentrations were observed in one or more cases for several nucleoside reverse transcriptase inhibitors (tenofovir, emtricitabine, lamivudine, zidovudine) and protease inhibitors (atazanavir, lopinavir, saquinavir et ritonavir); within individual twin pairs placental transfer was discordant for one or more ARVs, but identical for others.

Conclusion: Concentrations differed in nearly one third of twin pairs. This may be due to interindividual genetic variability of placental transporters between dizygotic twins as well as physiological differences between twins.

Abstract

Pregnancy and postpartum are high-risk periods for different forms of thrombotic microangiopathy (TMA). However, the management of pregnancy-associated TMA remains ill defined. This report, by an international multidisciplinary working group of obstetricians, nephrologists, hematologists, intensivists, neonatologists, and complement biologists, summarizes the current knowledge of these potentially severe disorders and proposes a practical clinical approach to diagnose and manage an episode of pregnancy-associated TMA. This approach takes into account the timing of TMA in pregnancy or postpartum, coexisting symptoms, first-line laboratory workup, and probability-based assessment of possible causes of pregnancy-associated TMA. Its aims are: to rule thrombotic thrombocytopenic purpura (TTP) in or out, with urgency, using ADAMTS13 activity testing; to consider alternative disorders with features of TMA (preeclampsia/eclampsia; hemolysis elevated liver enzymes low platelets syndrome; antiphospholipid syndrome); or, ultimately, to diagnose complement-mediated atypical hemolytic uremic syndrome (aHUS; a diagnosis of exclusion). Although they are rare, diagnosing TTP and aHUS associated with pregnancy, and postpartum, is paramount as both require urgent specific treatment.

Abstract

Endometriosis is a frequent, chronic, inflammatory gynecological disease characterized by the presence of ectopic endometrial tissue causing pain and infertility. Macrophages have a central role in lesion establishment and maintenance by driving chronic inflammation and tissue remodeling. Macrophages can be reprogrammed to acquire memory-like characteristics after antigenic challenge to reinforce or inhibit a subsequent immune response, a phenomenon termed « trained immunity. » Here, whereas bacille Calmette-Guérin (BCG) training enhances the lesion growth in a mice model of endometriosis, tolerization with repeated low doses of lipopolysaccharide (LPS^low) or adoptive transfer of LPS^low-tolerized macrophages elicits a suppressor effect. LPS^low-tolerized human macrophages mitigate the fibro-inflammatory phenotype of endometriotic cells in an interleukin-10 (IL-10)-dependent manner. A history of severe Gram-negative infection is associated with reduced infertility duration and alleviated symptoms, in contrast to patients with Gram-positive infection history. Thus, the manipulation of innate immune memory may be effective in dampening hyper-inflammatory conditions, opening the way to promising therapeutic approaches.

Abstract

We analyzed group B Streptococcus (GBS) neonatal invasive infections reported during 2007-2019 in France. The hypervirulent clonal complex (CC) 17 GBS was responsible for 66% (827/1,262) of cases. The role of CC17 GBS increased over time (p for trend = 0.0001), together with the emergence of a multidrug-resistant CC17 GBS sublineage.

J Gynecol Obstet Hum Reprod. 2020 Oct 31;101964. doi: 10.1016/j.jogoh.2020.101964.Online ahead of print.

Abstract

Objective: Assess the discordance between scalp pH and lactates performed from the same sample during labor.

Method: This single-center retrospective study included all women with a singleton fetus who had at least one fetal blood sample taken during labor. Some of them had up to seven samples. Scalp pH was the reference parameter for obstetric decision-making. The correlation between the pH and lactates was studied using Pearson coefficient. By categorizing the values as normal, pre-acidosis and acidosis, we were able to estimate agreement with Cohen’s kappa coefficient. The frequency of discordance in the categorization and the factors related to it were studied with univariate and multivariable analyses. Cases of severe acidosis at birth (cord pH < 7.00) and cases with acidosis scalp lactates but normal scalp pH were analyzed.

Results: We analyzed 480 samples from 268 fetuses among the 2644 deliveries during the study periode. Fetal blood sampling represented 10 % of deliveries. The scalp pH and lactates results were strongly correlated (r=-0.83), but their agreement was only fair (K = 0.36). In 29.4 % of cases, pH and lactates were discordant. Factors related to discordance were meconium-stained fluid, sampling at full dilation and multiple sampling. Six infants (2.2 %) had severe acidosis at birth. Cases’ analyses did not allow to conclude severe acidosis could have been avoided using scalp lactates for obstetric decision-making.

Conclusion: For more than a quarter of the samples, results were discordant between scalp pH and lactates, especially when cervix was full dilated and when the amniotic fluid was meconium-stained. A randomized controlled trial comparing the relevance of each parameter according to the obstetrical situation would be necessary.

Abstract

Background: Group B streptococcus (GBS) is a leading cause of sepsis, pneumonia and meningitis in infants, with long term neurodevelopmental sequelae. GBS may be associated with poor pregnancy outcomes, including spontaneous abortion, stillbirth and preterm birth. Intrapartum antibiotic prophylaxis (IAP) is currently the only way to prevent early-onset disease (presenting at 0 to 6 days of life), although it has no impact on the disease presenting over 6 days of life and its implementation is challenging in resource poor countries. A maternal vaccine against GBS could reduce all GBS manifestations as well as improve pregnancy outcomes, even in low-income countries.

Main body: The term « PREPARE » designates an international project aimed at developing a maternal vaccination platform to test vaccines against neonatal GBS infections by maternal immunization. It is a non-profit, multi-center, interventional and experimental study (promoted by the St George University of London. [UK]) with the aim of developing a maternal vaccination platform, determining pregnancy outcomes, and defining the extent of GBS infections in children and mothers in Africa. PREPARE also aims to estimate the protective serocorrelates against the main GBS serotypes that cause diseases in Europe and Africa and to conduct two trials on candidate GBS vaccines. PREPARE consists of 6 work packages. In four European countries (Italy, UK, Netherlands, France) the recruitment of cases and controls will start in 2020 and will end in 2022. The Italian PREPARE network includes 41 centers. The Italian network aims to collect: GBS isolates from infants with invasive disease, maternal and neonatal sera (cases); cord sera and GBS strains from colonized mothers whose infants do not develop GBS infection (controls).

Short conclusion: PREPARE will contribute information on protective serocorrelates against the main GBS serotypes that cause diseases in Europe and Africa. The vaccine that will be tested by the PREPARE study could be an effective strategy to prevent GBS disease.

Bull Epidémiol Hebd. 2020;(28):562-70. http://beh.santepubliquefrance.fr/beh/2020/28/2020_28_2.html

Résumé

Contexte : Malgré les bénéfices reconnus du lait maternel, les taux d’allaitement chez les enfants nés prématurément sont variables selon les pays et les unités néonatales. Les caractéristiques maternelles et néonatales associées à l’allaitement d’un enfant né prématurément ont largement été étudiées et n’expliquent pas l’ensemble de cette variabilité.

Objectifs : Décrire et analyser les facteurs associés à l’allaitement à la sortie d’hospitalisation chez les enfants nés prématurément, avec un intérêt particulier pour les politiques d’unités soutenant l’allaitement.

Méthodes : La cohorte Epipage-2 (Étude épidémiologique sur les petits âges gestationnels-2) est une étude nationale prospective en population ayant inclus les naissances survenues en 2011 entre 22 et 34 semaines d’aménorrhée (SA) dans toutes les unités néonatales de 25 régions françaises. Les déterminants de l’allaitement ont été analysés par régression logistique multivariée dans deux populations distinctes : 3 108 enfants nés avant 32 SA et 883 enfants nés entre 32 et 34 SA.

Résultats : Au total, 47% des enfants nés avant 32 SA et 59% des enfants nés entre 32 et 34 SA recevaient du lait maternel à la sortie d’hospitalisation, avec une variabilité inter-unités respective de 21% à 84% et de 27% à 87%. Les politiques d’unités soutenant l’allaitement, en particulier le peau-à-peau précoce, la participation des parents à l’alimentation de leur enfant, étaient en partie associées à cette variabilité. Des taux élevés d’initiation de l’allaitement dans la population générale n’étaient associés à l’allaitement à la sortie que chez les enfants nés entre 32 et 34 SA.

Conclusion : L’adoption des politiques de soutien des unités les plus performantes pourrait permettre de réduire la variabilité des taux d’allaitement à la sortie dans cette population à risque des enfants nés prématurément.

Abstract

Objective: To evaluate whether caesarean delivery before 26 weeks of gestation was associated with symptoms of depression and anxiety in mothers in comparison with deliveries between 26 and 34 weeks.

Design: Prospective national population-based EPIPAGE-2 cohort study.

Setting: 268 neonatology departments in France, March to December 2011.

Population: Mothers who delivered between 22 and 34 weeks and whose self-reported symptoms of depression (Center for Epidemiologic Studies Depression Scale: CES-D) and anxiety (State-Trait Anxiety Inventory: STAI) were assessed at the moment of neonatal discharge.

Methods: The association of caesarean delivery before 26 weeks with severe symptoms of depression (CES-D ≥16) and anxiety (STAI ≥45) was assessed by weighted and design-based log-linear regression model.

Main outcome measures: Severe symptoms of depression and anxiety in mothers of preterm infants.

Results: Among the 2270 women completing CES-D and STAI questionnaires at the time of neonatal discharge, severe symptoms of depression occurred in 25 (65.8%) women having a caesarean before 26 weeks versus in 748 (50.6%) women having a caesarean after 26 weeks. Caesarean delivery before 26 weeks was associated with severe symptoms of depression compared with caesarean delivery after 26 weeks (adjusted relative risk [aRR] 1.42, 95% CI 1.12-1.81) adjusted to neonatal birthweight and severe neonatal morbidity among other factors. There was no evidence of an association between mode of delivery and symptoms of anxiety.

Conclusions: Mothers having a caesarean delivery before 26 weeks’ gestation are at high risk of symptoms of depression and may benefit from specific preventive care.