Thesis (M.S.)--Brigham Young University. Dept. of Physiology and Developmental Biology, 2007. / Includes bibliographical references (p. 42-47).

Techn. Universiẗat, Diss., 2005--München.

Ritodrine is a beta-adrenergic agonist commonly used to inhibit premature labor contractions in women. The primary goal of ritodrine tocolysis is to prolong gestation, however, other indications may include fetal distress. The purpose of the current study was to examine the metabolic and behavioral effects of ritodrine in the fetus, using the chronically instrumented pregnant sheep as an experimental model. Ritodrine was infused continuously into 11 fetal lambs at a rate of 2.6 ug/minute for a period of 8, 12 or 24 hours. Samples were taken simultaneously at predetermined time periods from a fetal femoral artery, umbilical vein, maternal femoral artery and uterine vein for the analysis of fetal and maternal arterial and umbilical and uterine venous blood gases, acid-base status, hematocrit, ritodrine concentration, uterine and umbilical blood flow, and glucose, lactate and oxygen concentrations and fluxes. Cardiovascular and behavioral variables were monitored continuously. The average concentration of ritodrine in fetal arterial plasma was 20.0 ± 2.7 ng/ml (range 9.5 to 3 4.7 ng/ml) at the end of the infusion. This concentration is within the range of cord levels obtained in ritodrine exposed human fetuses at birth (7 to 79 ng/mL) . Fetal arterial plasma ritodrine levels at 8 hours post-infusion were still sufficiently elevated to exert considerable fetal effects. The apparent tolerance of the fetus to given plasma levels of drug varied considerably among animals. The infusion of ritodrine resulted in many typical beta-adrenergic receptor mediated responses in the fetus. Fetal arterial glucose levels rose to 79% above the control by the end of the infusion. This was associated with an increase in fetal glucose delivery (70% above the control), a decrease in the umbilical veno-arterial glucose concentration difference and a tendency for fetal glucose uptake to decline. Fetal arterial plasma lactate concentrations rose more than fivefold during the infusion of ritodrine. This was associated with a rise in fetal lactate delivery (540% above the control), a slight increase in the umbilical veno-arterial plasma lactate concentration difference and a tendency for fetal lactate uptake to rise. Fetal oxygen consumption rose progressively and significantly throughout the infusion of ritodrine and during the first 8 hours of post-infusion, reaching a maximum of 22% above the control by 8 hours post-infusion. Umbilical blood flow remained unchanged, therefore umbilical oxygen delivery was not increased to meet the additional oxygen demands of the fetus. The rise in fetal oxygen consumption was hence accomplished through an increase in fetal fractional oxygen extraction (from a control value of 32.0±1.1% to a maximum of 51.6±1.8% by 1.5 hours of infusion). The rise in fetal oxygen extraction resulted in concurrent declines in fetal arterial Po₂ (78% of the control) and O₂ content (55% of the control) and a widening of the veno-arterial oxygen content difference. By the end of the infusion, umbilical venous Po₂ and O₂ content values had also fallen significantly to 78% and 75% of the control respectively. These latter changes resulted in a concurrent 25% decline in fetal oxygen delivery which in turn contributed to the rise in fetal oxygen extraction. Fetal arterial and umbilical venous pH declined rapidly and significantly from control values of 7.370±0.004 and 7.401±0.005 to 7.274±0.025 and 7.306±0.023 respectively by the end of the infusion. The acidemia was reflected by significant declines in base excess values and appeared to be entirely metabolic in nature, resulting from elevated blood lactate levels. The acidemia likely contributed to the progressive fall in fetal blood O₂ content through a rightward shift of the oxyhemoglobin dissociation curve (Bohr effect). The rise in fetal oxygen consumption was reflected by a similar (although nonsignificant) increase in uterine oxygen consumption. Uteroplacental oxygen consumption appeared to remain unaltered. The rise in uterine oxygen consumption was not accompanied by a corresponding increase in uterine oxygen delivery, hence uterine oxygen extraction rose to 23.8±1.9% (from a control value of 19.5±1.6%) by 1.5 hours post-infusion. The rise in uterine oxygen extraction resulted in significant declines in uterine venous Po₂ and CO₂ values which likely contributed to the fall in fetal oxygen delivery. Fetal heart rate increased significantly to 21% (34 beats per minute, bpm) above the control (162±7 bpm) during the first 1.5 hours of ritodrine infusion. It remained elevated by an average of 16% (26 bpm) throughout the remainder of the infusion and the first 8 hours of post-infusion, returning to the control by the end of the post-infusion period. Fetal arterial pressure remained unchanged from the control (46.2±1.5 mm Hg). The incidence of fetal breathing activity fell significantly from an overall average control value of 43.2±2.6% to an average of 28.1±6.8% during the ritodrine infusion period. In most animals, breathing was most depressed near the end of the infusion. The incidence of low voltage electrocortical (ECoG) activity also fell significantly by an average of 7.5% while that of high voltage ECoG rose by 7.3%. Alterations in intermediate voltage activity were not observed. The incidence of fetal rapid eye movement also tended to fall by an average of 8.2% during the infusion of ritodrine. These behavioral changes may have resulted from the development of fetal hypoxemia, rather than as a direct effect of ritodrine. In conclusion, these data have demonstrated that ritodrine infusion to fetal lambs results in significant physiological and behavioral changes in the fetus. These effects may put the fetus at risk, particularly in situations where fetal oxygen delivery is already reduced, as in various states of compromised pregnancy. / Medicine, Faculty of / Obstetrics and Gynaecology, Department of / Graduate

An essential function of the placenta is the exchange of nutrients, and wasteproducts of fetal metabolism, between mother and fetus. The placenta thereforeplays a key role in determining fetal growth and size at birth. Fetal growthrestriction (FGR) is a complication affecting around 5% of pregnancies. Thereare several possible causes of FGR but the most common in the Western world isplacental dysfunction. The FGR baby is at much greater risk of stillbirth andneurodevelopmental morbidities than the normally grown baby. Furthermore, thesmaller baby per se has an increased risk of a range of morbidities as an adult.The thrust of the work covered in this thesis was to improve understanding of theabnormalities in placental exchange physiology associated with FGR. The goalwas (and is) to develop new placental diagnostic biomarkers for the disease andnew treatments based on improving placental function.The first tranche of work described showed that there are specific changes intransporter activities in the placenta in FGR. My colleagues and I showed thatSystem A amino acid transporter activity in the microvillous plasma membrane(MVM) of the syncytiotrophoblast (transporting epithelium of the placenta) isreduced, per mg membrane protein, and that this reduction is related to theseverity of the disease. This contrasted with our observation in normal pregnancythat MVM System A activity, per mg protein, is inversely related to size of the babyat birth, and first suggested the concept of placental adaptation to fetal growthdemand. We, and others, went on to show that a number of other transporters inthe syncytiotrophoblast are altered in FGR. However, not all transporters areaffected and at least one is upregulated. This led me to hypothesise that some ofthese changes are causal to FGR and some are responses, or adaptations, toabnormal fetal growth. The direct causes of transporter activity changes are notknown but our work, and that of others, suggests that glucocorticoids play a role.We also showed that transporter activities in the placenta are affected in othercomplications where fetal growth is aberrant. Furthermore, we provided evidencethat denuded areas of the syncytiotrophoblast might be the morphologicalcorrelate of a route of passive transfer of hydrophilic solutes across the placenta.Our studies in a mouse model of FGR suggest that abnormalities in such aparacellular route may be part of the placental dysfunction in the disease.In the final group of publications of this thesis I describe work showing gestationalchanges in placental transporter activities. I suggest that these are primarilyregulated to maintain fetal growth trajectory, but may also provide for specificnutrient demands at particular times in gestation. This explanation was supportedby work with genetically modified mice showing experimentally that placentaltransporter activity is regulated, or adapted, in relation to fetal growth demand. Itappears from several studies described here that there is a matching of fetalgrowth demand and placental nutrient supply. However, other work shows that thematernal nutritional environment does modify this matching.The studies described here have led to three ongoing lines of investigation: (1)applying knowledge of placental phenotypes of FGR to assist in early diagnosis ofwomen at risk; (2) using mouse models of FGR to test drugs for treating thedisease in humans; (3) investigations into the nature of the fetal nutrient demandsignal(s) to the placenta, and whether these signals are altered in FGR.

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published_or_final_version / Obstetrics and Gynaecology / Master / Master of Philosophy

published_or_final_version / Medicine / Master / Doctor of Medicine

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Diaplacentar deoxynivalenol intoxication in porcine fetuses. Are histomorphological and immunohistochemical investigations at the 70th day of gestation a helpful diagnostic tool?