Robert K. Creasy

Cardiovascular complications associated with terbutaline treatment for preterm labor

Severe cardiovascular complications occurred in eight of 160 patients treated with terbutaline for preterm labor. Associated corticosteroid therapy and twin gestations appear to be predisposing factors. Potential mechanisms of the pathophysiology are briefly discussed.

Experimental intrauterine growth retardation in the sheep

Abstract This report describes a procedure for investigation of the pathophysiology of fetal growth retardation in the sheep. In ewes with single fetuses (96 to 125 days gestation) a polyvinyl catheter was inserted into a distal branch of the uterine artery supplying the pregnant horn and cdvanced retrograde to the main uterine artery. Catheters were also placed in fetal blood vessels. Gradual embolization of the uteroplacental vascular bed was accomplished by injecting carbonised microspheres, 15 μ in diameter, into the uterine artery daily, if fetal blood gases were normal. When compared with control fetuses, the embolication group showed a mean decrease of 30 per cent in weight, variable decreases in certain organ weights, and a significant increase in the brain-to-liver weight ratio. In the embolization group, mean fetal Po 2 decreased 11 and 18 per cent, respectively, in each of the last two weeks of the study.

Oral ritodrine maintenance in the treatment of preterm labor

Seventy patients with preterm labor and intact membranes were initially treated with ritodrine hydrochloride to delay preterm delivery. Tocolysis beyond 24 hours was achieved in 59 patients. Fifty-five of the 59 patients were then placed on either oral ritodrine or placebo as maintenance therapy in a randomized double-blind manner. If preterm labor recurred, the sequence of intramuscular and then oral treatment was repeated. The number of days gained after initiation of intramuscular treatment was similar in both groups (oral ritodrine = 34 days, oral placebo = 36 days). In those 55 patients receiving oral treatment, there was a smaller number of relapses requiring repeat intramuscular treatment in the oral ritodrine group (1.11 in the ritodrine patient vs. 2.71 in the placebo patient, p less than 0.05), and the mean interval between beginning oral treatment and the first relapse/delivery was 5.8 days in the oral placebo group and 25.9 in those receiving oral ritodrine (p less than 0.05). Cardiovascular side effects, notably maternal tachycardia and palpitations were frequent but well tolerated. The results suggest that oral ritodrine maintenance will decrease the incidence of recurrent preterm labor in patients who have had initial successful tocolysis.

Responses of the growth-retarded fetus to acute hypoxemia

Growth retardation in the human fetus associated with maternal cardiovascular disease is frequently accompanied by birth asphyxia and perinatal mortality. We have investigated the cardiovascular responses to acute hypoxemia in the fetal lamb with growth retardation secondary to embolization of the uteroplacental vascular bed. In the basal period, fetal arterial P02 and umbilical perfusion were significantly lower, and perfusion of the adrenal glands, brain, and heart was significantly higher, in embolized than in control fetal lambs. During imposed acute hypoxemia there was preferential perfusion of vital organs, the adrenal glands, brain, and heart in control and embolized fetuses. This preferential perfusion to the vital organs during hypoxemia was significantly more pronounced in embolized animals. Because of the increased compensation during acute hypoxemia, as reflected by the increased preferential perfusion of vital organs, the growth-retarded fetuses would probably decompensate sooner if the hypoxemia was prolonged.

Lactate and Pyruvate as Fetal Metabolic Substrates

Extract: Whole blood lactate, pyruvate, and oxygen concentrations were measured simultaneously in the umbilical vein, fetal femoral artery, maternal artery, and uterine vein in 14 chronically catheterized pregnant ewes and their fetuses. Lactate was found to be taken up in significant amounts across the placental circulation by the fetuses, whereas pyruvate was not.The lactate concentration of fetal blood was higher than that of maternal blood; however, fetal lactate levels correlated with maternal arterial levels (P ≤ 0.01). The mean lactate concentrations in all samples were: common umbilical vein, 2.105 mM; fetal femoral artery, 1.986 mM; and maternal artery, 0.823 mM. Where uterine venous lactate concentrations were measured, the lactate content of the uterine vein exceeded that of the maternal artery by a mean of 0.088 mmol/liter (P < 0.005). The mean fetal gain in lactate across the placental circulation was 0.118 mmol/liter (P < 0.005). This is equivalent to a gain of 1.2 g carbon/kg/24 hr by the growing lamb fetus. The mean fraction of fetal oxygen consumption that could be accounted for by oxidation of lactate was 0.32.The pyruvate concentration of fetal blood was higher than that of maternal blood; however, fetal pyruvate levels correlated with maternal arterial levels (P < 0.05). The mean pyruvate concentrations in all samples were: common umbilical vein, 0.084 mM, fetal femoral artery, 0.094 mM; and maternal artery, 0.053 mM. Where uterine venous pyruvate concentrations were measured, they exceeded the maternal arterial concentrations by a mean of 0.005 mmol/liter (P = 0.001). Pyruvate appeared to be lost by the fetus across the placental circulation by a mean of 0.010 mmol/liter. This loss of pyruvate correlated with the placental fetal to maternal pyruvate concentration gradient (P < 0.05).Correlations between maternal arterial and fetal lactate concentrations imply that fetal lactate levels are influenced by maternal levels. The increase in lactate concentration of both fetal and maternal blood during circulation through the placenta indicates placental production of lactate. The pyruvate concentrations observed, however, are consistent with either fetal to maternal flow of pyruvate or placental productionSpeculation: Lactate, after glucose and amino acids, is the third most important fetal substrate identified in the fetal lamb. Its role as a fetal fuel now needs to be evaluated in other animal species.

Maternal morbidity associated with isoxsuprine and terbutaline tocolysis

A retrospective study of 343 women treated with isoxsuprine and/or terbutaline for preterm labor (PTL) was performed to determine the incidence and nature of maternal morbidity which is associated with this treatment. The incidence of mild cardiovascular (CV), neurological and gastrointestinal side effects was similar with both medications. The incidence, however, of severe CV complications such as pulmonary edema and myocardial ischemia was higher among women treated with i.v. terbutaline (5.3%) than among those treated with isoxsuprine (0.8%, P less than 0.05). Patients with multiple gestations on i.v. terbutaline therapy had an exceptionally high incidence of severe CV complications (43%), while none of the twin pregnancies on i.v. isoxsuprine had such complications. Corticosteroid treatment was not associated with a significant increase of complications with either tocolytic medication. Both medications had similar success in inhibiting PTL.

Cardiac and uterine hemodynamic responses to ritodrine hydrochloride administration in pregnant sheep

The changes in the maternal circulation following administration of ritodrine hydrochloride were investigated in chronically prepared pregnant sheep. Low infusion rates of ritodrine (see text) elevated the maternal heart rate and cardiac output and decreased peripheral vascular resistance. Stroke work fell while minute work increased. The distribution of uterine blood flow did not change, as measured with microspheres. Simultaneously measured fetal cardiac output and umbilical blood flow were not altered. When ritodrine infusion rates (see text) were increased there was a slight but significant decrease in uterine perfusion pressure, and an increase in uterine vascular resistance with uterine blood flow decreasing. These changes were observed when the ewes were not in labor, and similar changes were again recovered with ewes in labor despite the simultaneous inhibition of uterine contractions. Selective beta blockade with practolol during ritodrine administration decreased the maternal tachycardia without affecting cardiac output, peripheral vascular resistance, or uterine vascular resistance.

Cardiac output and its distribution and organ blood flow in the fetal lamb during ritodrine administration

The response of the fetal circulation to beta adrenergic stimulation with ritodrine hydrochloride has been investigated by long-term monitoring of the fetal lamb in utero. Ritodrine was infused intravenously either into the ewe or directly into the fetus, and cardiovascular and acid-base responses were measured. Fetal cardiac output and its distribution were measured with the use of radionuclide-labeled microspheres. The output of each ventricle also was measured by means of long-standing implanted electromagnetic flow transducers around the ascending aorta or pulmonary trunk during infusion of ritodrine at various rates into the fetus. Infusion of ritodrine (1.9 mcg. per kilogram per minute) into the ewe caused no change in fetal heart rate, blood pressure, cardiac output, or umbilical blood flow, but did cause an increase in fetal adrenal and myocardial blood flow. Ritodrine infused directly into the fetus produced a marked increase in fetal heart rate and a minimal change in cardiac output. There were no significant changes in fetal or maternal acid-base balance during the ritodrine infusions.

Effect of ritodrine on uterine activity, heart rate, and blood pressure in the pregnant sheep: Combined use of alpha or beta blockade

Ritodrine hydrochloride was administered parenterally to pregnant ewes during spontaneous or oxytocin-induced uterine activity. The effects of ritodrine on the uterus and cardiovasculature were assessed both with and without simultaneous administration of either alpha or beta blockade. Ritodrine was found to be an effective inhibitor of both spontaneous and induced uterine activity. Ritodrine did cause maternal tachycardia but no significant hypotension. Alpha-adrenergic blockade did not influence the effects of ritodrine. Beta blockade with propranolol reversed the uterine and cardiovascular effects of ritodrine, whereas beta blockade with practolol reversed the cardiovascular effects without interfering with the inhibition of uterine activity produced by ritodrine.

Hyperfibrinogenemia and polycythemia with intrauterine growth retardation in fetal lambs

Plasma concentrations of albumin and fibrinogen and arterial hematocrits were determined during the last third of gestation in growth-retarded and control fetal lambs. The mean fetal plasma albumin concentration increased slightly as term approached and was not significantly different in the two groups. The mean plasma fibrinogen concentration did not change in the control fetuses, but was significantly elevated in the growth-retarded fetuses, as was the mean arterial hematocrit. The theoretical implications of these findings relative to capillary blood flow are discussed.