Research
Obstetrics
Vitamin C supplementation ameliorates the adverse effects of nicotine on placental hemodynamics and histology in nonhuman primates

Presented in oral format at the 35th annual meeting of the Society for Maternal-Fetal Medicine, San Diego, CA, Feb. 2-8, 2015, and at the 34th annual meeting of the Society for Maternal-Fetal Medicine, New Orleans, LA, Feb. 3-8, 2014. The racing flag logo above indicates that this article was rushed to press for the benefit of the scientific community.
https://doi.org/10.1016/j.ajog.2014.12.042Get rights and content

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.

Study Design

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.

Conclusion

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.

Section snippets

Experimental design

Time-mated female Rhesus macaques (n = 27) were randomly allocated to control (n = 5), nicotine only (n = 4), vitamin C only (n = 9), or nicotine plus vitamin C groups (n = 9). On gestational day 26 of pregnancy, control animals received subcutaneous (midscapular) Alzet miniosmotic 2ML4 pumps containing bacteriostatic water (Abbott Laboratories, North Chicago, IL), and nicotine animals received subcutaneous osmotic minipump infusions of nicotine bitartrate (Sigma, St. Louis, MO) in

Results

Nicotine and cotinine levels in maternal serum, amniotic fluid, and cord blood at the time of delivery are shown in Table 1. Maternal plasma levels were similar in both groups. Nicotine and cotinine were undetectable in the amniotic fluid from control animals. Nicotine levels were significantly higher in the amniotic fluid of the vitamin C plus nicotine group, whereas cotinine showed a less notable increase, compared with the nicotine-only group.

Maternal, fetal birth, and placental weights are

Comment

We found that prenatal nicotine exposure significantly reduced overall fetal blood supply, which corresponded with significant histological findings characteristic of placental hypoxia. These effects were ameliorated in nicotine-exposed animals that received maternal vitamin C supplementation. The presence of nicotine, however, did not significantly alter maternal perfusion of the placenta.

Prenatal nicotine exposure has been associated with fetal hypoxia in utero.43 Our finding of decreased cQUV

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    This study was supported by National Institutes of Health grants R01 HL087710, R21-HD076265, and P51 OD011092-53.

    The authors report no conflicts of interest.

    Cite this article as: Lo JO, Schabel MC, Roberts VHJ, et al. Vitamin C supplementation ameliorates the adverse effects of nicotine on placental hemodynamics and histology in nonhuman primates. Am J Obstet Gynecol 2015;212:370.e1-8.

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