Adverse Placental Perfusion and Pregnancy Outcomes in a New Nonhuman Primate Model of Gestational Protein Restriction

Abstract

Maternal malnutrition during pregnancy impacts fetal growth, with developmental consequences that extend to later life outcomes. In underdeveloped countries, this malnutrition typically takes the form of poor dietary protein content and quality, even if adequate calories are consumed. Here, we report the establishment of a nonhuman primate model of gestational protein restriction (PR) in order to understand how placental function and pregnancy outcomes are affected by protein deficiency. Rhesus macaques were assigned to either a control diet containing 26% protein or switched to a 13% PR diet prior to conception and maintained on this PR diet throughout pregnancy. Standard fetal biometry, Doppler ultrasound of uteroplacental blood flow, ultrasound-guided amniocentesis, and contrast-enhanced ultrasound (CE-US) to assess placental perfusion were performed mid-gestation (gestational day 85 [G85] where term is G168) and in the early third trimester (G135). Our data demonstrate that a 50% reduction in dietary protein throughout gestation results in reduced placental perfusion, fetal growth restriction, and a 50% rate of pregnancy loss. In addition, we demonstrate reduced total protein content and evidence of fetal hypoxia in the amniotic fluid. This report highlights the use of CE-US for in vivo assessment of placental vascular function. The ability to detect placental dysfunction, and thus a compromised pregnancy, early in gestation, may facilitate the development of interventional strategies to optimize clinical care and improve long-term offspring outcomes, which are future areas of study in this new model.

Micro-anatomic alterations of the placenta in a non-human primate model of gestational protein-restriction

“…These findings are consistent with, not proof of causation of, the adverse pregnancy outcomes noted in the parent study [15] where adverse placental perfusion was demonstrated. While we were able to detect significant associations between maternal diet and the placental micro-vasculature, our findings have many strengths and limitations that must be understood.…”

“…Using these methods [17], our aim for this study was to histologically characterize the micro-vascular alterations associated with these adverse pregnancy outcomes in our NHP model of gestational protein-restriction (PR). Our prior published work with this model when pregnancies continued to natural delivery at term [15], demonstrated fetal growth restriction by ultrasound biometry at 135 days of gestation, which is the gestational age at which the placental samples were collected in the current study. Having previously demonstrated decreased perfusion with reduced maternal dietary protein content, we hypothesized that by 3D imaging we would find compromised vascular development in the placental villi.…”

“…The development and findings for our NHP model of gestational PR has been previously published [15]. Placental samples obtained and analyzed for this work were part of a larger animal study examining the impact of gestational protein restriction on maternal, placental and fetal outcomes.…”

“…Our group has previously developed a model of protein-malnutrition in the non-human primate (NHP) [ 15 ] which is highly suitable as a translational animal model due to the similarity in placental vasculature and fetal development [ 16 ]. In these well-characterized, highly controlled NHP pregnancies we demonstrated evidence of decreased placental perfusion, fetal hypoxia, fetal growth restriction and stillbirth in those pregnancies exposed to a 50% reduction in dietary protein before and during the pregnancy [ 15 ]. Previous efforts to understand the mechanisms underlying how malnutrition can result in poor placental development and function have been limited.…”

Gadolinium Chelate Safety in Pregnancy: Barely Detectable Gadolinium Levels in the Juvenile Nonhuman Primate after in Utero Exposure

“…Animals were allowed to breed naturally, and pregnancies were identified early in the first trimester with routine two-dimensional ultrasonography (US) (Voluson 730 Expert; GE Medical Systems, Kretztechnik, Austria), with fetal biometry measurements used for gestational dating. These animals were part of a study to determine the effects of gestational protein restriction on pregnancy outcomes and placental function (26).…”