ABSTRACT
Nowadays, antiretroviral therapy is recommended during pregnancy to prevent mother-to-child transmission of HIV. However, for many antiretroviral drugs, including maraviroc, a CCR5 antagonist, very little data exist regarding placental transfer. Besides, various factors may modulate this transfer, including efflux transporters belonging to the ATP-binding cassette (ABC) transporter superfamily. We investigated maraviroc placental transfer and the influence of ABC transporter expression on this transfer using the human cotyledon perfusion model. Term placentas were perfused ex vivo for 90 min with maraviroc (600 ng/ml) either in the maternal-to-fetal (n = 10 placentas) or fetal-to-maternal (n = 6 placentas) direction. Plasma concentrations were determined by ultra performance liquid chromatography coupled with tandem mass spectrometry (UPLC-MS/MS). Fetal transfer rates (FTR) and clearance indexes (CLI) were calculated as ratios of fetal to maternal concentrations at steady state (mean values between 30 and 90 min) and ratios of FTR of maraviroc to that of antipyrine, respectively. ABC transporter gene expression levels were determined by quantitative reverse transcription (RT)-PCR and ABCB1 protein expression by Western blotting. For the maternal-to-fetal direction, the mean FTR and CLI were 8.0% ± 3.0 and 0.26 ± 0.07, respectively, whereas the mean CLI was 0.52 ± 0.23 for the fetal-to-maternal direction. We showed a significant inverse correlation between maraviroc CLI and ABCC2, ABCC10, and ABCC11 placental gene expression levels (P < 0.05). To conclude, we report a low maraviroc placental transfer probably involving ABC efflux transporters and thus in all likelihood associated with a limited fetal exposition. Nevertheless, these results would need to be supported by in vivo data obtained from paired maternal and cord blood samples.
Subject(s)
Cyclohexanes/metabolism , Gene Expression , HIV Fusion Inhibitors/metabolism , Models, Biological , Placenta/metabolism , Triazoles/metabolism , ATP Binding Cassette Transporter, Subfamily B , ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , ATP-Binding Cassette Transporters/genetics , ATP-Binding Cassette Transporters/metabolism , Chromatography, Liquid , Cyclohexanes/pharmacology , Diffusion Chambers, Culture , Female , Fetus , HIV Fusion Inhibitors/pharmacology , Humans , Kinetics , Maraviroc , Maternal-Fetal Exchange , Multidrug Resistance-Associated Protein 2 , Multidrug Resistance-Associated Proteins/genetics , Multidrug Resistance-Associated Proteins/metabolism , Organ Culture Techniques , Perfusion , Placenta/drug effects , Pregnancy , Tandem Mass Spectrometry , Triazoles/pharmacologyABSTRACT
OBJECTIVE: To assess the risk of uterine rupture in case of uterine scar in specific situations. To investigate whether ultrasonographic measurement of the lower uterine segment is predictive of the risk of uterine rupture. METHODS: French and English publications were identified through PubMed and Cochrane databases. RESULTS: Trial of labor after cesarean (TOLAC) is possible in cases of uterine mullerian anomalies, segmental vertical or unknown uterine incision, postpartum fever, cesarean delivery before 37 weeks during the previous cesarean (professional agreement). TOLAC can be considered if obstetrical conditions are favorable even if the delay is less than 6 months between the previous cesarean delivery and the date of conception of the following pregnancy (professional agreement). TOLAC can be considered after a previous myomectomy, depending on technical conditions under which the intervention was conducted (gradeC). TOLAC is possible even after previous hysteroscopic metroplasty for uterine septa or in cases of uterine perforation with monopolar coagulation (professional agreement). The type of uterine suture during the previous cesarean should not influence the choice of the route of delivery (professional agreement). TOLAC can be considered in cases of two previous cesarean sections if obstetrical conditions are favorable (professional agreement). Planned cesarean section is recommended from history of three previous cesarean sections (professional agreement). A planned cesarean section is recommended in cases of previous corporeal incision during cesarean (gradeC). There is not enough data to recommend ultrasonographic measurement of the lower uterine segment during pregnancy to help to determine the route of delivery (professional agreement). CONCLUSIONS: TOLAC can be considered, depending on obstetric conditions, in all situations studied, except in cases of previous obstetric corporeal incision or previous history of at least three cesareans.
