Aims: To enhance understanding of betamethasone and its metabolites' pharmacokinetics in pregnancy, specifically early‐onset pre‐eclampsia, through a population pharmacokinetic model. Additionally, to investigate the placental metabolism and transfer of betamethasone and its main metabolites.Methods: A prospective, single‐centre pharmacokinetic study was conducted in pregnant women (n = 28) with imminent preterm birth treated with intramuscular betamethasone. Betamethasone serum concentrations were determined from serial venous blood samples (n = 194). Placental transfer and metabolism were studied using ex vivo human placental perfusion (healthy term; n = 3) and placental explant experiments (healthy term, n = 4; early‐onset pre‐eclampsia, n = 4). Additionally, placental mRNA expression of CYP3A4, CYP3A7, 11β‐hydroxysteroid dehydrogenase (HSD) 1 and 11β‐HSD2 were quantified in healthy and early‐onset pre‐eclampsia placentas.Results: The population pharmacokinetic model was best described by a 2‐compartment nonlinear mixed effects model. Betamethasone clearance in early‐onset pre‐eclamptic women was 60% lower of that observed in women without pre‐eclampsia (9.35 vs. 15.78 L/h), resulting in a 40% median increase in maternal betamethasone exposure (1567 vs. 1114 ng h/mL). Ex vivo experiments showed placental transfer of betamethasone to the foetal circulation (foetal‐to‐maternal ratio 0.76 ± 0.05 [in a perfused placental cotyledon]). The placenta only converted betamethasone into 11‐ketobetamethasone, with similar ratios in early‐onset pre‐eclampsia and healthy placental explants (3.0 ± 2.2 vs. 1.4 ± 0.4 per mg tissue, P = .27). The expression of 11β‐HSD1 mRNA was lower in early‐onset pre‐eclampsia placentas (P = .015), while placental CYP3A7 and 11β‐HSD2 mRNA expression were similar.Conclusion: Women with early‐onset pre‐eclampsia have elevated betamethasone exposure. Betamethasone transfers freely into the foetal circulation, with placental metabolism resulting only in 11‐ketobetamethasone. Decreased placental 11β‐HSD1 expression may play a role in increased betamethasone exposure in early‐onset pre‐eclampsia.

BACKGROUND: The endocannabinoid system (ECS) plays an important role in the early stages of pregnancy, while cannabis use during pregnancy associates with a greater risk of preeclampsia. This study quantified the placental ECS component mRNA levels in gestational age-matched healthy pregnant women, women with preeclampsia, and women who used cannabis throughout their pregnancy. Next, it compared the effects of the endogenous ECS agonists anandamide and 2-arachidonoylglycerol with those of the cannabinoid receptor type 1 and 2 agonists HU-210 and HU-308 in chorionic plate arteries. METHODS: Placental mRNA levels were quantified by quantitative polymerase chain reaction. Vascular reactivity was studied with and without selective cannabinoid receptor type 1 and 2 antagonists. RESULTS: mRNA levels of 1,2-diacylglycerol lipase α, responsible for 2-arachidonoylglycerol generation, were lowered in preeclampsia, while mRNA levels of the anandamide-synthesizing enzyme N -acyl phosphatidylethanolamine-specific phospholipase D were upregulated in cannabis users. Anandamide-induced relaxation in healthy pregnancy was mediated via cannabinoid receptors type 1 and 2, while 2-arachidonoylglycerol induced relaxation via cannabinoid receptor type 1. In preeclampsia, the effects of anandamide and 2-arachidonoylglycerol were unaltered but no longer involved cannabinoid receptors, while in cannabis users their effects were absent. HU-210 and HU-308 relaxed healthy, but not preeclamptic vessels. The NO donor sodium nitroprusside similarly relaxed healthy and preeclamptic vessels, while its effects in cannabis users were greatly reduced. CONCLUSIONS: The ECS is disturbed in preeclampsia, and endogenous ECS agonists lose their capacity to dilate in cannabis users, while such use also diminishes NO signaling. These data provide mechanistic evidence against cannabis use during pregnancy.

The use of cannabis during pregnancy is increasing, in line with its growing societal acceptance and legalization. Cannabis use mainly concerns its active components Δ⁹-tetrahydrocannabinol (THC) and cannabidiol (CBD). While cannabis has therapeutic effects on pain, nausea, and vomiting, its impact on fetal development remains a significant public health concern. Given the existence of a local endocannabinoid system (ECS) in the placenta, with proven effects on placental development and blood flow, it is likely that THC and CBD exert effects via interference with the placental ECS. This review summarizes how cannabis use affects the placental ECS and describes the consequences of such use on placental function and fetal development. It starts with discussing the placental ECS, the effects of THC and CBD on placental function, and the pharmacokinetics of cannabinoids during pregnancy. It then describes the effects of both paternal and maternal cannabis use and provides epidemiological data linking placental insufficiency, impaired fetal growth, and preeclampsia to cannabis use. It also raises awareness for the possibility that cannabis use, by altering DNA methylation, might result in transgenerational effects. It is concluded that current evidence supports abstaining from cannabis use during preconception, pregnancy, and lactation to optimize maternal, fetal, and intergenerational health outcomes.

Cannabis use is increasing among pregnant women, although such use associates with fetal growth restriction and preeclampsia. While most research focuses on Δ9-tetrahydrocannabinol (THC), many pregnant women use cannabidiol (CBD)-containing products like CBD-oils. It is unknown whether CBD is transferred across the placenta. CBD transfer was studied using an ex vivo placental perfusion model, making use of healthy term placentas. CBD was added to the maternal side. Placentas were perfused for 180 minutes. Using liquid chromatography-tandem mass spectrometry, CBD was quantified in perfusates and post-perfusion biopsies. Vascular reactivity of CBD and THC was determined in chorionic plate arteries using wire-myography with and without antagonists for the 2 types of CB receptors (CB1 and CB2). CBD concentrations in the maternal buffer dropped by >80% within 30 minutes due to rapid oxidation and remained undetectable in fetal samples. Albumin in combination with the anti-oxidant sodium ascorbate prevented this rapid drop. With albumin and sodium ascorbate being present, CBD transfer to the fetal side could be observed, reaching a fetal/maternal ratio of 0.32±0.23, while 11±4% was recovered in tissue. Furthermore, CBD dilated healthy placental arteries by 36±4%. This was attenuated by AM251 (CB1 receptor antagonist) and AM630 (CB2 receptor antagonist). THC induced vasoconstriction in the presence of AM251. Rapid oxidation of CBD can be prevented by adding an antioxidant. Under those conditions, CBD transfers to the fetus. CBD dilates fetoplacental vessels, while THC induces constriction. These data may help to understand potential risks of cannabis use in pregnancy.