Objective 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 linking altered placental function to impaired fetal development remain areas of active research. Recently, we developed MRI techniques in nonhuman primates to characterize placental blood oxygenation through measurements of T2*, and perfusion using dynamic contrast-enhanced (DCE) MRI. 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. Study Design Timed-pregnant Rhesus macaques (n=12) were divided into 2 groups: control (n=6) and ethanol exposed (n=6). Animals were trained to orally self-administer either 1.5g/kg/day of a 4% ethanol solution (equivalent to 6 drinks/day) or an isocaloric control fluid from pre-conception until gestational day 60 (G60, term is G168). All underwent Doppler ultrasound (D-US) followed by MRI consisting of T2* and DCE measurements. D-US was used to measure uterine artery (Uta) and umbilical vein velocimetry and diameter to calculate Uta volume blood flow (cQuta) and placental volume blood flow (cQuv). After non-invasive imaging, animals underwent C-section delivery for placenta collection and fetal necropsy at G110 (n=6) or G135 (n=6). Results Fetal weight and biparietal diameter were significantly smaller in ethanol exposed compared to controls at G110. By D-US, cQuta was decreased (p=0.1) and cQuv was significantly lower (p=0.04) at both G110 and G135 in ethanol exposed versus control animals. A significant reduction in placental blood flow was evident by DCE-MRI. As we demonstrated recently, T2* values vary throughout the placenta, and reveal gradients in blood deoxyhemoglobin concentration ranging 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 at G110 (p=0.02). Fetal brain measurements indicated impaired growth and development at G110, but less so at G135 in ethanol exposed vs. control. Conclusion 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 G135 than at G110. These findings are consistent with placental adaptation to early perturbations allowing for compensated placental function and maintenance of fetal growth.

In conclusion, FGF21 reduced body weight in obese rhesus macaque monkeys without reducing food intake. Furthermore, FGF21 had beneficial effects on body composition, insulin sensitivity, and plasma triglycerides. No adverse effects on bone density or plasma cortisol were observed after 12 weeks of treatment.

Background The utero-placental vascular supply is a critical determinant of placental function and fetal growth. Current methods for the in vivo assessment of placental blood flow are limited. Objective Here we demonstrate the feasibility of utilizing contrast-enhanced ultrasound to visualize and quantify perfusion kinetics in the intervillous space of the primate placenta. Study design Pregnant Japanese macaques were studied at mid second trimester and in the early third trimester. Markers of injury were assessed in placenta samples from animals with or without contrast-enhanced ultrasound exposure (n=6/group). Human subjects were recruited immediately prior to scheduled first trimester pregnancy termination. All studies were performed with maternal intravenous infusion of lipid-shelled octofluoropropane microbubbles with image acquisition using a multipulse contrast-specific algorithm with destruction-replenishment analysis of signal intensity for assessment of perfusion. Results In macaques, rate of perfusion in the intervillous space was increased with advancing gestation. No evidence of microvascular hemorrhage or acute inflammation was found in placental villous tissue and expression levels of caspase-3, nitrotyrosine and HSP70 as markers of apoptosis, nitrative and oxidative stress respectively were unchanged by contrast-enhanced ultrasound exposure. In humans, placental perfusion was visualized at 11wks gestation and preliminary data reveal regional differences in intervillous space perfusion within an individual placenta. By electron microscopy, we demonstrate no evidence of ultrastructure damage to the microvilli on the syncytiotrophoblast following first trimester ultrasound studies. Conclusions Use of contrast-enhanced ultrasound did not result in placental structural damage, and was able to identify intervillous space perfusion rate differences within a placenta. Contrast-enhanced ultrasound may offer a safe clinical tool for the identification of pregnancies at-risk for vascular insufficiency; early recognition may facilitate intervention and improved pregnancy outcomes.