Research Article: Hypoglycemia and the Origin of Hypoxia-Induced Reduction in Human Fetal Growth

Date Published: January 1, 2010

Publisher: Public Library of Science

Author(s): Stacy Zamudio, Tatiana Torricos, Ewa Fik, Maria Oyala, Lourdes Echalar, Janet Pullockaran, Emily Tutino, Brittney Martin, Sonia Belliappa, Elfride Balanza, Nicholas P. Illsley, Wen-Liang Zhou.

Abstract: The most well known reproductive consequence of residence at high altitude (HA >2700 m) is reduction in fetal growth. Reduced fetoplacental oxygenation is an underlying cause of pregnancy pathologies, including intrauterine growth restriction and preeclampsia, which are more common at HA. Therefore, altitude is a natural experimental model to study the etiology of pregnancy pathophysiologies. We have shown that the proximate cause of decreased fetal growth is not reduced oxygen availability, delivery, or consumption. We therefore asked whether glucose, the primary substrate for fetal growth, might be decreased and/or whether altered fetoplacental glucose metabolism might account for reduced fetal growth at HA.

Partial Text: Abnormalities of fetal growth cost billions per year in neonatal intensive care, maternal hospital admissions and lost work productivity for the worried parents. The subsequent financial and social costs due to long-term damage to the fetus, e.g. physical handicaps and/or diminished cognitive abilities, are inestimable [1]. Intrauterine growth restriction (IUGR) affects 3–10% of pregnancies with rates steadily increasing in the USA [2]; 20% of stillborn infants have IUGR [3]. Perinatal mortality rates are 4–8 times higher for growth retarded infants, and morbidity is present in 50% of surviving infants [3], [4], [5], [6]. To date no intervention other than delivery has proved effective. A common underlying contributor to IUGR is placental hypoxia due to impaired placental invasion of maternal blood vessels and/or poor placental vascular development that diminishes the fetal vascular surface area available for oxygen diffusion [7]. Determining the effects of chronic hypoxia on human fetoplacental metabolism and growth has long presented a challenge, due not only to ethical concerns and problems of accessibility, but because hypoxia is almost always present in combination with additional pathologies such as abnormal placental development or preeclampsia. The natural experiment afforded by human residence at high altitude allows us to study fetal and placental responses to chronic hypoxia in the absence of these additional pathologies. This report describes fetal glucose delivery and consumption in low and high altitude pregnancies in which we have carefully documented the fact that there is no fetal oxygen deficit at high altitude and thus that hypoxia is not the proximate cause of the reduction in fetal growth.

The birth weight of neonates at 3600 m is reduced >300 g compared to low altitude pregnancies, despite the fact that maternal and fetal oxygen delivery and fetal oxygen consumption do not differ between altitudes. Maternal glucose delivery to the placenta did not differ between altitudes but both umbilical venous and arterial glucose concentrations were significantly decreased at high altitude. This was associated with a >28% reduction in fetal glucose consumption, a 37% decrease in median fetal plasma insulin concentrations and a trend towards fetal lactacidemia at high altitude. The hypothesis that reduced fetal weight was associated with decreased fetal glucose delivery and consumption was supported. The hypothesis that increased metabolism of glucose by the placenta contributes to the reduction in glucose consumption was supported by the observation of decreased delivery of glucose to the high altitude fetus despite a greater maternal arterial to fetal arterial gradient. Finally, the hypothesis that there might be increased anaerobic metabolism of glucose by the placenta at high altitude was supported by decreased delivery of glucose in the absence of changes in oxygen delivery to placenta and fetus. The amount of glucose delivered to the fetus was strongly associated with the amount of glucose consumed, presumably contributing to the growth (or lack thereof) of the fetus. The relationship between glucose delivery and consumption was far more pronounced at high altitude, suggesting that glucose dependency in the high altitude fetus may be increased relative to the low-altitude fetus. In contrast, the amount of insulin secreted relative to fetal glucose concentrations did not differ between altitudes, indicating that decreased fetal growth is not attributable to alterations in the fetal insulin response. These results lead us to conclude that the reduction in fetal growth due to chronic hypoxia is mediated not by limitations on oxygen availability, but by fetal hypoglycemia and its consequences. The model of high altitude pregnancy reveals that an initiating step in IUGR may be decreased glucose delivery to the fetus, presumably as a result of the increased placental consumption of the glucose delivered by the mother to the uteroplacental circulation.



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