First trimester alcohol exposure alters placental perfusion and fetal oxygen availability affecting fetal growth and development in a non-human primate model.
Prenatal alcohol exposure leads to impaired fetal growth, brain development, and stillbirth. Placental impairment likely contributes to these adverse outcomes, but the mechanisms and specific vasoactive effects of alcohol that links altered placental function to impaired fetal development remain areas of active research.



Recently, we developed magnetic resonance imaging techniques in nonhuman primates to characterize placental blood oxygenation through measurements of T2* and perfusion using dynamic contrast-enhanced magnetic resonance imaging. The objective of this study was to evaluate the effects of first-trimester alcohol exposure on macaque placental function and to characterize fetal brain development in vivo.



Timed-pregnant Rhesus macaques (n=12) were divided into 2 groups: control (n=6) and ethanol exposed (n=6). Animals were trained to self-administer orally either 1.5 g/kg/d of a 4% ethanol solution (equivalent to 6 drinks/d) or an isocaloric control fluid from preconception until gestational day 60 (term is G168). All animals underwent Doppler ultrasound scanning followed by magnetic resonance imaging that consisted of T2* and dynamic contrast-enhanced measurements. Doppler ultrasound scanning was used to measure uterine artery and umbilical vein velocimetry and diameter to calculate uterine artery volume blood flow and placental volume blood flow. After noninvasive imaging, animals underwent cesarean delivery for placenta collection and fetal necropsy at gestational day 110 (n=6) or 135 (n=6).



Fetal weight and biparietal diameter were significantly smaller in ethanol-exposed animals compared with control animals at gestational day 110. By Doppler ultrasound scanning, placental volume blood flow was significantly lower (P=.04) at gestational day 110 in ethanol-exposed vs control animals. A significant reduction in placental blood flow was evident by dynamic contrast-enhanced magnetic resonance imaging. As we demonstrated recently, T2* values vary throughout the placenta and reveal gradients in blood deoxyhemoglobin concentration that range from highly oxygenated blood (long T2*) proximal to spiral arteries to highly deoxygenated blood (short T2*). Distributions of T2*throughout the placenta show significant global reduction in T2* (and hence high blood deoxyhemoglobin concentration) in ethanol-exposed vs control animals at gestational day 110 (P=.02). Fetal brain measurements indicated impaired growth and development at gestational day 110, but less so at gestational day 135 in ethanol-exposed vs control animals.



Chronic first-trimester ethanol exposure significantly reduces placental perfusion and oxygen supply to the fetal vasculature later in pregnancy. These perturbations of placental function are associated with fetal growth impairments. However, differences between ethanol-exposed and control animals in placental function and fetal developmental outcomes were smaller at gestational day 135 than at gestational day 110. These findings are consistent with placental adaptation to early perturbations that allow for compensated placental function and maintenance of fetal growth.
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 Reproductive & Developmental Sciences, Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR.
Victoria H J
VH
Roberts
Division of Neuroscience, Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR.
Xiaojie
X
Wang
Division of Reproductive & Developmental Sciences, Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR.
Katherine S
KS
Lewandowski
Division of Neuroscience, Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR.
Kathleen A
KA
Grant
Department of Obstetrics and Gynecology, Oregon Health & Science University, Portland, OR; Division of Reproductive & Developmental Sciences, Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR.
Antonio E
AE
Frias
Advanced Imaging Research Center, Oregon Health & Science University, Portland, OR; Division of Neuroscience, Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR.
Christopher D
CD
Kroenke
D000818:Animals; D000431:Ethanol / Q000009:adverse effects*; D005260:Female; D047109:Fetal Development / Q000187:drug effects*; D005333:Fetus / Q000187:drug effects* / Q000378:metabolism*; D008253:Macaca mulatta; D008279:Magnetic Resonance Imaging; D023421:Models, Animal; D010100:Oxygen / Q000378:metabolism*; D021041:Placental Circulation / Q000187:drug effects* / Q000502:physiology*; D011247:Pregnancy; D011261:Pregnancy Trimester, First; D016216:Ultrasonography, Prenatal
D000431:Ethanol; D010100:Oxygen
alcohol; imaging; nonhuman primate; oxygenation; placental perfusion