Delineating the effects of prenatal oxycodone exposure and melatonin treatment on placental and fetal outcomes in pregnant rats

Background: Prenatal oxycodone (oxy) exposure has been associated with adverse pregnancy and fetal developmental outcomes. In this study, we assessed whether chronic prenatal oxy exposure impairs placental and fetal growth in rats and if maternal melatonin supplementation would mitigate these effects. Methods: Female Sprague-Dawley rats received either saline or oxy via oral gavage for 15 days before mating (10-15mg/kg dose escalation) and throughout pregnancy (15mg/kg). From gestational day (GD) 12.5, half of the dams received melatonin (10mg/kg). On GD19.5, maternal and fetal blood, and maternal, placental and fetal tissues were harvested. Placental histomorphometry was assessed and immunohistochemistry for pan-cytokeratin, PCNA, CD34, α-SMA, and TUNEL analysis were performed. Maternal and fetal plasma cytokines, angiogenic factors, and pregnancy hormones were measured by ELISA. Anthropometric data were analyzed using general linear mixed models and other outcomes were analyzed using univariate general linear models. Results: Oxy induced fetal growth restriction as evidenced by reduced placental weight, fetal weight, fetal-to-placental weight ratio, crown-rump length, and fetal liver weight. Melatonin also independently reduced some parameters of fetal growth but when administered with oxy it partially improved fetal outcomes including the head-to-abdominal diameter ratio. Oxy exposure increased placental labyrinth zone area, the percentage of CD34-positive cells, and maternal plasma IL-1β and IL-10 concentrations and reduced the percentage of pan-cytokeratin positive cells, while both oxy and melatonin reduced maternal plasma chorionic gonadotropin levels. Conclusion: Prenatal oxy exposure disrupts placental structure, labyrinth anatomy, and induces maternal systemic inflammation, associated with impaired fetal growth. The protective effects of melatonin are partial but indicate a potential brain sparing effect.