Maternal and Neonatal Tolerance of Antiretroviral Treatment During Pregnancy in the HAART Era

L’objectif de cette thèse était d’étudier les associations potentielles entre les traitements antirétroviraux reçus par les femmes enceintes infectées par le VIH et les complications pouvant survenir au cours de la grossesse ou être diagnostiquées dans la période néonatale. Ce travail est issu en majeure partie des données de l’Enquête Périnatale Française (ANRS-EPF), cohorte nationale multicentrique ayant inclus plus de 20 000 couples mères-enfants depuis 1986. Actuellement, presque toutes les femmes sont traitées par combinaisons antirétrovirales puissantes (cART ; 98% en 2013) et le taux de transmission est inférieur à 1% : 0.6% (IC95% : 0.4%-0.8% pour la période 2005-2013). La première partie portait sur le risque d’accouchement prématuré dont le taux a augmenté significativement entre la période 1990-1993 et 2005-2009, passant de 9.2% à 14.3%. Le risque d’accouchement prématuré était significativement associé au traitement par cART, par rapport aux monothérapies et bithérapies d’INTI, et au traitement débuté avant la conception par rapport aux traitements débutés en cours de grossesse. La survenue d’une cytolyse hépatique était fréquente (17%), et était liée à la fois à la prématurité, et au type de traitement, plus fréquentes avec les IP qu’avec les inhibiteurs non nucléosidiques de la transcriptase inverse. La perturbation du bilan hépatique pourrait être un facteur intermédiaire dans la relation entre traitements et accouchement prématuré. La seconde partie portait sur les malformations congénitales. D’une part, elle a permis de mettre en évidence une association entre exposition à l’efavirenz au premier trimestre de grossesse et les malformations neurologiques, bien que concernant peu de cas (n=4) et n’atteignant la significativité que dans une analyse de sensibilité. Cette association incite à maintenir une vigilance chez les enfants exposés in utero à cette molécule classée tératogène par la FDA mais prescrite de plus en plus largement. D’autre part, l’exposition au premier trimestre à la zidovudine était associée à la survenue de malformations cardiaques. La troisième partie a complété cette étude par une analyse de la fonction cardiaque, des modifications infracliniques de la contractilité et de l’épaisseur des parois du ventricule gauche ont été mises en évidence chez les enfants exposés in utero à une combinaison de traitement contenant la zidovudine et la lamivudine. Ces résultats ne remettent pas en question l’efficacité majeure des traitements antirétroviraux pour la prévention de la transmission de la mère à l’enfant du VIH, mais incitent à la poursuite d’une surveillance épidémiologique des effets indésirables potentiels, de manière à optimiser les prescriptions pour un meilleur rapport bénéfice/risque.Our objective was to study potential associations between antiretroviral treatment and obstetrical or neonatal complications in a population of HIV-positive pregnant women. Most of the analyses were conducted with data from the French Perinatal Cohort (ANRS-EPF), an ongoing multicenter national cohort with more than 20 000 mother-infant pairs included since 1986. In the recent years, most women receive combination antiretroviral therapies (cART ; 98% en 2013) and the trasnsmission rate is consistently under 1% : 0.6% (IC95% : 0.4%-0.8% for 2005-2013). Risk of preterm birth was significantly associated with cART, when compared to NRTI monotherapy or dual therapy, and with timing of treatment, higher for women treated at conception than for those initiating treatment during pregnancy. The occurrence of liver enzyme elevation was frequent (17%), and was associated both with preterm birth and with PI-based treatment, when compared to NNRTIs. LEE could be an intermediate factor between cART and preterm birth. The second part of this work was a study of congenital birth defect in the cohort, and showed an association between first trimester-exposure to efavirenz and neurological defects, but this concerned small numbers (n=4), and reached significance only in a sensitivity analysis. This association encourages us to maintain awareness concerning this molecule, considered teratogenic by the FDA but more and more largely prescribed. We also reported an association between first-trimester exposure to zidovudine and congenital heart defects. In a third part, we studied heart function, differences in contractility and septum thickness of the left ventricle was found, among girls exposed to a combination containing zidovudine and lamivudineThese results do not question the great progress of antiretroviral treatment in the prevention of mother-to-child transmission, but they encourage us to continue epidemiologic surveillance of potential side effects, in order to optimize prescriptions for an improved benefit/risk ratio

Tolérance maternelle et néonatale des antirétroviraux pendant la grossesse à l’ère des multithérapies

Our objective was to study potential associations between antiretroviral treatment and obstetrical or neonatal complications in a population of HIV-positive pregnant women. Most of the analyses were conducted with data from the French Perinatal Cohort (ANRS-EPF), an ongoing multicenter national cohort with more than 20 000 mother-infant pairs included since 1986. In the recent years, most women receive combination antiretroviral therapies (cART ; 98% en 2013) and the trasnsmission rate is consistently under 1% : 0.6% (IC95% : 0.4%-0.8% for 2005-2013). Risk of preterm birth was significantly associated with cART, when compared to NRTI monotherapy or dual therapy, and with timing of treatment, higher for women treated at conception than for those initiating treatment during pregnancy. The occurrence of liver enzyme elevation was frequent (17%), and was associated both with preterm birth and with PI-based treatment, when compared to NNRTIs. LEE could be an intermediate factor between cART and preterm birth. The second part of this work was a study of congenital birth defect in the cohort, and showed an association between first trimester-exposure to efavirenz and neurological defects, but this concerned small numbers (n=4), and reached significance only in a sensitivity analysis. This association encourages us to maintain awareness concerning this molecule, considered teratogenic by the FDA but more and more largely prescribed. We also reported an association between first-trimester exposure to zidovudine and congenital heart defects. In a third part, we studied heart function, differences in contractility and septum thickness of the left ventricle was found, among girls exposed to a combination containing zidovudine and lamivudineThese results do not question the great progress of antiretroviral treatment in the prevention of mother-to-child transmission, but they encourage us to continue epidemiologic surveillance of potential side effects, in order to optimize prescriptions for an improved benefit/risk ratio.L’objectif de cette thèse était d’étudier les associations potentielles entre les traitements antirétroviraux reçus par les femmes enceintes infectées par le VIH et les complications pouvant survenir au cours de la grossesse ou être diagnostiquées dans la période néonatale. Ce travail est issu en majeure partie des données de l’Enquête Périnatale Française (ANRS-EPF), cohorte nationale multicentrique ayant inclus plus de 20 000 couples mères-enfants depuis 1986. Actuellement, presque toutes les femmes sont traitées par combinaisons antirétrovirales puissantes (cART ; 98% en 2013) et le taux de transmission est inférieur à 1% : 0.6% (IC95% : 0.4%-0.8% pour la période 2005-2013). La première partie portait sur le risque d’accouchement prématuré dont le taux a augmenté significativement entre la période 1990-1993 et 2005-2009, passant de 9.2% à 14.3%. Le risque d’accouchement prématuré était significativement associé au traitement par cART, par rapport aux monothérapies et bithérapies d’INTI, et au traitement débuté avant la conception par rapport aux traitements débutés en cours de grossesse. La survenue d’une cytolyse hépatique était fréquente (17%), et était liée à la fois à la prématurité, et au type de traitement, plus fréquentes avec les IP qu’avec les inhibiteurs non nucléosidiques de la transcriptase inverse. La perturbation du bilan hépatique pourrait être un facteur intermédiaire dans la relation entre traitements et accouchement prématuré. La seconde partie portait sur les malformations congénitales. D’une part, elle a permis de mettre en évidence une association entre exposition à l’efavirenz au premier trimestre de grossesse et les malformations neurologiques, bien que concernant peu de cas (n=4) et n’atteignant la significativité que dans une analyse de sensibilité. Cette association incite à maintenir une vigilance chez les enfants exposés in utero à cette molécule classée tératogène par la FDA mais prescrite de plus en plus largement. D’autre part, l’exposition au premier trimestre à la zidovudine était associée à la survenue de malformations cardiaques. La troisième partie a complété cette étude par une analyse de la fonction cardiaque, des modifications infracliniques de la contractilité et de l’épaisseur des parois du ventricule gauche ont été mises en évidence chez les enfants exposés in utero à une combinaison de traitement contenant la zidovudine et la lamivudine. Ces résultats ne remettent pas en question l’efficacité majeure des traitements antirétroviraux pour la prévention de la transmission de la mère à l’enfant du VIH, mais incitent à la poursuite d’une surveillance épidémiologique des effets indésirables potentiels, de manière à optimiser les prescriptions pour un meilleur rapport bénéfice/risque

Evaluation of a policy of restrictive episiotomy on the incidence of perineal tears among women with spontaneous vaginal delivery: A ten-year retrospective study

International audienceIntroduction: Routine episiotomy is no longer recommended to limit obstetrical anal sphincter injuries (OASIs). We aimed to evaluate the effect of a restrictive policy of episiotomy on the risk of OASIs during spontaneous vaginal deliveries.Material and methods: We performed a retrospective single-center observational study among women with a term singleton cephalic fetus, with spontaneous vaginal delivery. The occurrence of episiotomy, intact perineum, first, second, third or fourth-degree (OASIs) perineal tears were compared before (period A, from 01/01/2006 to 12/31/2008) and after (period B, from 01/01/2012 to 12/31/2016) implementation of the restrictive policy. Odds of perineal tear were estimated using multivariable logistic regression models, stratified by parity.Results: From 2006-2016, the rate of episiotomy decreased, from 14.9 % (n/N = 200/1141) to 4.7 % (94/1912). In period B (N = 8984) vs A (N = 8984), the rates of episiotomy were, 12.9 vs 26.6 % for nulliparas (p < 0.01) and 2.3 vs 6.8 % for multiparas (p < 0.01). Odds of OASIs were not different in period B vs A, both for nulliparas (0.9 vs 0.8 %, AOR = 0.88(0.38-2.05)) and multiparas (0.4 vs 0.2 %, AOR = 2.28(0.63-8.29). Odds of second-degree tear were higher in period B vs A, both for nulliparas (39.8 vs 17.4 %, AOR = 2.55 (2.11-3.08) and multiparas (26.2 vs 12.8 %, AOR = 2.26(1.95-2.66)); and odds of intact perineum were lower (for nulliparas, 15.8 vs 24.9 %, AOR = 0.61(0.42-0.90) and for multiparas, 47.1 vs 56.0 %, AOR = 0.61 (0.49-0.76)). No difference was observed for first-degree tears.Conclusion: The progressive implementation of a restrictive policy of episiotomy during spontaneous vaginal delivery was not associated with an increased risk of OASIs over a ten-year period. (C) 2020 Elsevier Masson SAS. All rights reserved

Placental transfer and safety in pregnancy of medications under investigation to treat coronavirus disease 2019

International audienceOBJECTIVE: Treatment of coronavirus disease 2019 is mostly symptomatic, but a widerange of medications are under investigation against severe acute respiratory syndrome coronavirus 2. Although pregnant women are excluded from clinical trials, they willinevitably receive therapies whenever they seem effective in nonpregnant patients andeven 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, azi-thromycin, and some monoclonal antibodies. However, some drugs are strictly prohibitedin 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 potentialanti-severe acute respiratory syndrome coronavirus 2 drugs, several medications can already be used in pregnant women

Hygiene measures as primary prevention of toxoplasmosis during pregnancy: A systematic review

International audienceBackground Hygiene measures are recommended to prevent toxoplasmosis during pregnancy, although screening for seroconversion in pregnant women currently are debated and practices vary among countries. Objectives The purpose of this systematic literature review was to assess the effectiveness of hygiene measures during pregnancy to prevent toxoplasmosis infection. Search Strategy We followed the standard MOOSE and PRISMA criteria when conducting this systematic review and reporting the results. Selection criteria A systematic literature search was conducted for studies focused on congenital toxoplasmosis prevention, toxoplasmosis prevention during pregnancy, toxoplasmosis prevention and hygiene measures, which were published between 1970 and August 2020, using the databases of PubMed, Scope Med, EMBASE, and the Cochrane library. Data collection and analysis Our literature search identified 3964 articles, 3757 were excluded after review of title or abstract and 67 studies were considered relevant to the subject. We reviewed risk factors for toxoplasmosis infection during pregnancy and for congenital toxoplasmosis, preventive measures for toxoplasmosis during pregnancy, including: dietary recommendations, pet care measures, environmental measures, knowledge of risk factors and ways to control toxoplasmosis infection, knowledge of risk factors for infection by health professionals, knowledge of primary prevention measures by pregnant women. Conclusion: Hygiene measures are effective and applicable primary prevention to reduce toxoplasmosis and avoid congenital toxoplasmosis and its consequences

Low Birth Weight Is Strongly Associated with the Risk of Deep Infiltrating Endometriosis: Results of a 743 Case-Control Study

International audienceThe influence of intrauterine environment on the risk of endometriosis is still controversial. Whether birth weight modifies the risk of endometriosis in adulthood remains an open ques-tion. For this purpose, we designed a case-control study involving 743 women operated on for benign gynecological indications from January 2004 to December 2011. Study group in-cluded 368 patients with histologically proven endometriosis: 54 superficial endometriosis (SUP), 79 endometriomas (OMA) and 235 deep infiltrating endometriosis (DIE). Control group included 375 patients without endometriosis as surgically checked. Mean birth weights were compared between patients and controls, according to endometriosis groups and rAFS stages. Mean birth weight was significantly lower for patients with endometriosis as compared to controls (3,119g ± 614 and 3,251g ± 557 respectively; p = 0.002). When compared to controls, patients with DIE had the lowest birth weight with a highly significant difference (3,103g ± 620, p = 0.002). In univariate analysis, patients with low birth weight (LBW), defined as a BW < 2,500g, had a higher risk of endometriosis, especially DIE, as compared to the reference group (OR = 1.5, 95%CI: 1.0-2.3 and OR = 1.7, 95%CI: 1.0-2.7, respectively). Multivariate analysis, adjusted on ethnicity and smoking status, showed the persistence of a significant association between endometriosis and LBW with a slight in-crease in the magnitude of the association (aOR = 1.7, 95%CI: 1.0-2.6 for endometriosis, aOR = 1.8; 95%CI: 1.1-2.9 for DIE). In conclusion, LBW is independently associated with the risk of endometriosis in our population. Among patients with LBW, the risk is almost two-times higher to develop DIE. This association could reflect common signaling pathways be-tween endometriosis and fetal growth regulation. There is also the possibility of a role played by placental insufficiency on the development of the neonate's pelvis and the occur-rence of neonatal uterine bleeding that could have consequences on the risk of severe endometriosis

Placental growth factor for the prediction of adverse outcomes in patients with suspected preeclampsia or intrauterine growth restriction.

The circulating concentration of PlGF is reported to be lower in patients experiencing preeclampsia and patients delivering a small for gestational age (SGA) neonate. To evaluate the predictive value of circulating PlGF for preeclampsia and adverse outcome in patients with suspected preeclampsia or intrauterine growth restriction (IUGR).A double blind prospective study. We enrolled 96 women for suspected preeclampsia or IUGR, and measured plasma levels of PlGF (Triage®) at enrolment. We defined adverse outcome as severe preeclampsia, SGA neonate (<10(th) centile) or elective delivery for maternal or fetal complication. Severe adverse outcome was studied among patients included <34 weeks gestation (WG) and defined as eclampsia, HELLP syndrome, very SGA (<3(rd) centile) or elective delivery <34 WG. The mean logtransformed PlGF level was lower for women who experienced preeclampsia (2.9 vs 3.7, p = 0.02), and was markedly lower for patients who experienced adverse outcome (2.9 vs 4.3, p<0.001). The odds of presenting an adverse outcome were higher for the lowest tertile of PlGF compared to the higher (OR = 13 , 95% CI [3-50]). For severe adverse outcome, odds were respectively for the lowest and intermediate tertile as compared with the higher tertile : OR = 216, 95% CI [18-2571]; and OR = 17, 95% CI [3-94]. When included <34 WG, patients with a PlGF level <12 pg/ml experienced a severe adverse outcome in 96% of cases (24/25), and only 1 of 20 patients with a PlGF level >5(th) centile experienced a severe adverse outcome within 15 days (5%).Among women with suspected preeclampsia or IUGR, PlGF helps identify women who will experience an adverse outcome and those who will not within a time period of 15 days

Liver Enzyme Elevation in Pregnant Women Receiving Antiretroviral Therapy in the ANRS-French Perinatal Cohort

International audienceBACKGROUND:High rates of liver enzyme elevation (LEE) in women receiving antiretroviral treatment (ART) during pregnancy have been reported but causes remain unclear. We estimated the prevalence and risk factors of LEE in a national prospective multicenter cohort.METHODS:We studied 5748 pregnant women living with HIV enrolled in the French Perinatal Cohort 2005-2014, treated with ART, with no active hepatitis B or C co-infection. Adjusted hazard ratio (aHR) were estimated using Cox models with ART as time-dependent variable, separately for women on ART at conception and those initiating ART during pregnancy.RESULTS:LEE (grade>1) was observed in 16.7%, grade 3-4 in 2%. Among women with LEE, 6.7% had preeclampsia, 9.8% intrahepatic cholestasis of pregnancy, and 1.4% other identified medical causes. Most LEE (82.2%) were unexplained. In women with unexplained LEE, LEE was the reason for hospitalization in 51 (6%) women, cesarean section in 13 (2%), induction of labour in 3 (0.4%), and change in ART regimen in 49 (6%) women. Unexplained LEE was associated with higher risk of preterm births, p<0.001.Among women on ART at conception, the risk of unexplained LEE was lower with NNRTI-based regimens than with PI-based regimens: aHR=0.5[0.3-0.7], with no difference among the PI drugs. Most women initiating ART during pregnancy were on a PI-based regimen (89%). Among them, LEE was less frequent for women on nelfinavir vs. lopinavir/r (aHR=0.4[0.2-0.8]).CONCLUSION:Rates of LEE among pregnant women living with HIV are high and impact obstetrical care management. The possible role of PIs needs further investigation