Maternal cannabis use during pregnancy associates with alterations in placental endocannabinoid- and steroid-homeostasis and morphology.

BACKGROUND

Maternal cannabis use associates with adverse pregnancy outcomes including preeclampsia. Human data on cannabis-associated disruption of the placental endocannabinoid system (ECS) are lacking.

METHODS

We studied placentas from women with frequent cannabis use throughout pregnancy and non-exposed controls. Ex vivo dual-sided cotyledon perfusion was used to assess maternal and fetal release of cannabinoids, ECS-related lipid mediators, prostaglandins, and steroids by LC-ESI-MS/MS. Placental gene expression was quantified by RT-qPCR and placental histopathology was compared in cannabis users, non-smoking controls and tobacco-exposed pregnancies.

RESULTS

The major cannabis-component Δ9-tetrahydrocannabinol (THC) was detectable in placental tissue and released maternally and fetally. Cannabis use was associated with altered placental release of ECS-related lipids, including enhanced fetal release of N-acylethanolamines and loss of normal maternal-fetal release polarity for several lipid mediators. Cannabis-exposed placentas showed lower tissue concentrations of cortisone, membrane phospholipids, and selected mono- and diglycerides, suggesting reduced substrate availability for endogenous ECS lipid generation. Maternal cortisol release was increased, while HSD3B1 expression was upregulated without corresponding increases in progesterone content. Histopathological analyses showed reduced placental weight, umbilical cord length, and maximal placental diameter, with increased marginal or peripheral cord insertion, accelerated maturation, ischemia, and chorioamnionitis in cannabis-exposed placentas.

CONCLUSIONS

Cannabis use during pregnancy is associated with placental accumulation and fetal-side release of THC, altered ECS-related lipid signaling, disturbed steroid profiles, and placental structural abnormalities. These findings may help explain previously reported associations between prenatal cannabis exposure and placental dysfunction and warn against cannabis use during pregnancy.