PARENT SESSION

(MS42) TESTING THE LIMITS OF MATERNAL-FETAL PARTNERSHIP: ADAPTIVE SUCCESS AND FAILURE UNDER CONDITIONS OF CHRONIC HYPOXIA IN HUMAN PREGNANCY.

Zamudio, Stacy¹, Caniggia, Isabella², Illsley, Nicholas³, ¹ New Jersey Medical School, Newark, NJ² Samuel Lunenfeld Research Institute, Toronto, ON, Canada³ New Jersey Medical School, Newark, NJ

ABSTRACT- Human pregnancy at high altitude (HA) is a natural experimental model to test the limits of flexibility in placental, maternal and fetal cooperation. HA residence reduces fetal growth (100 grams/1000 m elevation), increases the incidence of preeclampsia 2-4 fold, and, in the absence of high quality medical care, increases maternal, fetal and neonatal mortality. We review here how populations with a long evolutionary history at HA have adapted to the stress of lowered oxygen availability and have ameliorated, but not fully overcome the altitude-associated reduction in fetal growth. This involves fetal, maternal and placental changes related to reduced oxygen availability. At the physiological level, women of HA ancestry have increased blood flow and oxygen delivery to the fetus. Fetuses of HA ancestry have increased oxygen uptake that is proportional to their greater growth, regardless of altitude. Placental structural alterations and maternal and fetal vascular and hematological changes yield greater uteroplacental and fetal blood flows, higher oxygen saturation of the fetal blood and ultimately greater oxygen delivery and uptake in fetuses of HA ancestry. While this contributes to preservation of fetal growth at HA (and larger infants at low altitude), the compensation is not complete, and even the newborns of a genetically adapted population are smaller than their sea level counterparts. At the molecular level there is dissociation of some of the expected effects of hypoxia on placental development and function. Elevated placental hypoxia-inducible factor 1 alpha (HIF-1alpha) message and protein expression are directly correlated with maternal and placental factors relevant to pregnancy outcome at HA, including placental capillary density, maternal circulating VEGF and erythropoietin levels. Elevation in HIF-1alpha in the HA placenta likely contributes to increased placental vascularity, but basal syncytial membrane glucose and amino acid transporter densities are reduced. With respect to glucose this contrasts with in vitro studies and suggests that factors either indirectly related to hypoxia or separate from hypoxia contribute to the reduction in fetal growth at HA, despite preservation of oxygen delivery in the pregnancies of well-adapted populations. Support NSF BCS 0309142, NIH HD 42737.

KEY WORDS: human fetal growth, hypoxia inducible factors, nutrient transport, placenta