Vitamin C supplementation ameliorates the adverse effects of nicotine on placental hemodynamics and histology in nonhuman primates.
OBJECTIVE
We previously demonstrated that prenatal nicotine exposure decreases neonatal pulmonary function in nonhuman primates, and maternal vitamin C supplementation attenuates these deleterious effects. However, the effect of nicotine on placental perfusion and development is not fully understood. This study utilizes noninvasive imaging techniques and histological analysis in a nonhuman primate model to test the hypothesis that prenatal nicotine exposure adversely effects placental hemodynamics and development but is ameliorated by vitamin C.


METHODS
Time-mated macaques (n = 27) were divided into 4 treatment groups: control (n = 5), nicotine only (n = 4), vitamin C only (n = 9), and nicotine plus vitamin C (n = 9). Nicotine animals received 2 mg/kg per day of nicotine bitartrate (approximately 0.7 mg/kg per day free nicotine levels in pregnant human smokers) from days 26 to 160 (term, 168 days). Vitamin C groups received ascorbic acid at 50, 100, or 250 mg/kg per day with or without nicotine. All underwent placental dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) at 135-140 days and Doppler ultrasound at 155 days to measure uterine artery and umbilical vein velocimetry and diameter to calculate uterine artery volume blood flow and placental volume blood flow. Animals were delivered by cesarean delivery at 160 days. A novel DCE-MRI protocol was utilized to calculate placental perfusion from maternal spiral arteries. Placental tissue was processed for histopathology.


RESULTS
Placental volume blood flow was significantly reduced in nicotine-only animals compared with controls and nicotine plus vitamin C groups (P = .03). Maternal placental blood flow was not different between experimental groups by DCE-MRI, ranging from 0.75 to 1.94 mL/mL per minute (P = .93). Placental histology showed increased numbers of villous cytotrophoblast cell islands (P < .05) and increased syncytiotrophoblast sprouting (P < .001) in nicotine-only animals, which was mitigated by vitamin C.


CONCLUSIONS
Prenatal nicotine exposure significantly decreased fetal blood supply via reduced placental volume blood flow, which corresponded with placental histological findings previously associated with cigarette smoking. Vitamin C supplementation mitigated the harmful effects of prenatal nicotine exposure on placental hemodynamics and development, suggesting that its use may limit some of the adverse effects associated with smoking during pregnancy.
Department of Obstetrics and Gynecology, Oregon Health & Science University, Portland, OR. Electronic address: loj@ohsu.edu.
Jamie O
JO
Lo
Advanced Imaging Research Center, Oregon Health & Science University, Portland, OR.
Matthias C
MC
Schabel
Division of Diabetes, Obesity, and Metabolism, Oregon National Primate Research Center, Portland, OR.
Victoria H J
VH
Roberts
Department of Pathology, Oregon Health & Science University, Portland, OR.
Terry K
TK
Morgan
Department of Obstetrics and Gynecology, Oregon Health & Science University, Portland, OR.
Juha P
JP
Rasanen
Advanced Imaging Research Center, Oregon Health & Science University, Portland, OR; Division of Neuroscience, Oregon National Primate Research Center, Portland, OR.
Christopher D
CD
Kroenke
Division of Diabetes, Obesity, and Metabolism, Oregon National Primate Research Center, Portland, OR.
Sophie R
SR
Shoemaker
Division of Neuroscience, Oregon National Primate Research Center, Portland, OR.
Eliot R
ER
Spindel
Department of Obstetrics and Gynecology, Oregon Health & Science University, Portland, OR; Division of Diabetes, Obesity, and Metabolism, Oregon National Primate Research Center, Portland, OR; Division of Reproductive and Developmental Sciences, Oregon National Primate Research Center, Portland, OR.
Antonio E
AE
Frias
D000818:Animals; D001205:Ascorbic Acid / Q000008:administration & dosage / Q000494:pharmacology*; D019587:Dietary Supplements; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005731:Ganglionic Stimulants / Q000008:administration & dosage / Q000009:adverse effects*; D008251:Macaca; D008279:Magnetic Resonance Imaging; D018811:Maternal Exposure / Q000009:adverse effects*; D009538:Nicotine / Q000008:administration & dosage / Q000009:adverse effects*; D010920:Placenta / Q000098:blood supply / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000473:pathology; D021041:Placental Circulation / Q000187:drug effects*; D011247:Pregnancy; D011897:Random Allocation; D018615:Ultrasonography, Doppler, Color; D014815:Vitamins / Q000008:administration & dosage / Q000494:pharmacology*
D005731:Ganglionic Stimulants; D014815:Vitamins; D009538:Nicotine; D001205:Ascorbic Acid
nicotine; nonhuman primate; noninvasive imaging; placental perfusion; vitamin C