(172) Prenatal Oxycodone Exposure and its Effects on Fetal and Placental Outcomes in the Rat

Hager M. Kowash¹, Isaac Adediji¹, Pegah Nouri Mousa¹, Victoria L. Schaal², Gurudutt Pendyala², Lynda K. Harris¹.

< !1.   Department of Obstetrics and Gynecology, University of Nebraska Medical Center, Omaha, US.

< !2.   Department of Anesthesiology, University of Nebraska Medical Center, Omaha, US.

 

Abstract Text:

Prenatal maternal opioid use poses significant risks to the fetus associated with increased incidence of fetal growth restriction, preterm delivery and impairments in cognition and behavior in later life. We hypothesize that prenatal exposure to oxycodone, known to have a high placental transfer rate relative to other opioids, will alter placental function and fetal neurodevelopment, and that melatonin treatment may mitigate associated detrimental effects.

Nulliparous female Sprague Dawley rats were randomly allocated to receive saline or oxycodone by oral gavage for 10 days prior to mating, at a starting dose of 10mg/kg/day, steadily increased by 0.5mg/kg/day for 10 days to reach a final dose of 15mg/kg/day. This dosing regimen was then continued during mating and throughout gestation. A subset of animals in each of the groups was also treated with melatonin daily from gestational day (GD) 12.5. Placentas, fetuses and fetal tail tips were harvested on GD19.5. Placental and fetal weights and fetal anthropometric measures were recorded. Fetuses were sextyped using PCR amplification of the male Sry gene from tail tips. Placentas were stained with haematoxylin and eosin and the junctional (JZ) and labyrinth (LZ) zone areas quantified using Image J. Immunohistochemistry was performed on placental sections against specific antibodies including TUNEL (apoptosis), PCNA (proliferation) and pan-cytokeratin (trophoblast cells).

Litter size, number of resorptions and sex-distribution was unaffected by both exposure to oxycodone and/or treatment with melatonin. Maternal percentage bodyweight increase from baseline throughout gestation was higher in dams that received melatonin. At GD19.5, melatonin had the effect of significantly increasing fetal weight (P< 0.01), irrespective of exposure to oxycodone or saline.  Oxycodone exposure significantly reduced placenta weight (P< 0.05). Fetal:Placental (F:P) weight ratio, a marker of placental transport efficiency, was reduced by oxycodone exposure and increased by melatonin treatment (P< 0.001). Melatonin treatment increased crow-rump length and abdominal and head diameter (P< 0.001). Oxycodone exposure had no significant effect on crown-rump length or head diameter but was associated with significantly smaller fetal abdominal diameters compared to saline (P< 0.001). Further, head:abdominal diameter ratio was significantly increased by oxycodone exposure (P< 0.001). Melatonin treatment, but not oxycodone exposure, significantly decreased JZ area (P=0.026) and increased both LZ area (P=0.016) the LZ:JZ ratio (P=0.014). Quantitative analysis of TUNEL, PCNA and pan-cytokeratin staining showed no difference in the number of positively stained cells from saline and oxycodone-treated placentas and no effect of treatment with melatonin.

Whilst others have shown oxycodone exposure to be associated with FGR, we did not observe this in this small pilot cohort of animals, although we did find a decreased placental weight and F:P weight ratio. Further, we showed oxycodone increases head to abdomen ratio, a phenomenon known in small for gestational age fetuses. Melatonin shows promise as a therapeutic with potentially beneficial effects of increasing fetal weight and anthropometric measures, as well as increasing placental LZ area, which in turn, could advantageously increase the surface area for exchange. Whilst we report no significant effects on proliferation, apoptosis or trophoblast cell numbers as per the immunohistochemical markers measured, ongoing work aims to further characterize effects of oxycodone exposure and melatonin treatment on specific placental cell subtypes and other markers of interest.