Summary report on the NICHD research planning Workshop on Physical Activity in Pregnancy.
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Biomedical subjects
J F Clapp
Publications and source records attributed to J F Clapp.
Endurance exercise and pregnancy outcome.
The interaction between maternal endurance exercise at or above a minimal conditioning level, prior to and during pregnancy, and pregnancy outcome was examined prospectively in our obstetrical populace using epidemiologic techniques. Over a 3-month interval all women registering for antepartum care were interviewed. Those planning to continue exercise during pregnancy were re-interviewed between the 28th and 34th gestational weeks. A detailed review of clinical records was used for outcome assessment. Women who continued endurance exercise at or near preconceptual levels during pregnancy gained less weight (-4.6 kg), delivered earlier (-8 d), and had lighter-weight offspring (-500 g) than those who stopped exercising prior to the 28th week. The latter group gained 2.2 kg more weight but delivered similar birthweight infants at a similar gestational age as their sedentary controls.
Adolescent↗
The uterine hemodynamic response to repetitive unilateral vascular embolization in the pregnant ewe.
The longitudinal hemodynamic response of the uterine circulation to pregnancy and to repetitive embolic insult was assessed in 23 singleton ewe pregnancies by means of electromagnetic flow transducers and radionuclide-labeled microspheres. The data indicate that the longitudinal hemodynamic changes observed in the uterine circulation were directly related to the growth rate of the tissue which it supplied. The hemodynamic impact of embolization appears to be secondary to its impact on tissue growth. Embolization simply blunts the normal incremental increases in uterine perfusion and the cross-sectional area of the uterine vascular bed. It alters actual tissue perfusion only within a portion of the cotyledonary circulation. Finally, the data support the presence of functional arterial anastomoses between the two sides of the uterine circulation in this species.
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The ovine fetoplacental endocrine response to placental damage.
In the chronic pregnant ewe preparation, daily blood samples, for the determination of plasma cortisol and progesterone levels by specific radioimmunoassay, were obtained from the fetal distal aorta, uterine vein, and uterine artery prior to, during, and after repetitive embolization of the uterine circulation with 15 mu microspheres. A significant increase in fetal cortisol was observed in all animals during the first 3 days of embolization. In those which subsequently entered premature labor, this increase was progressive and was associated with a fall in the uterine venous progesterone level but was unrelated to changes in either the maternal cortisol level or fetal physiologic parameters. In animals which did not enter premature labor, progesterone levels in the uterine vein and estimated progesterone release rates were elevated with an accentuated peak-trough pattern during the postembolization period. In these animals fetal cortisol returned to control levels. The data suggest that cortisol and progesterone biosynthesis within the fetoplacental unit is altered by microembolic placental damage.
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Adult haematopoietic cells transplanted to sheep fetuses continue to produce adult globins.
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Animals↗
Fetal death in utero: effect on estrone, estradiol-17 beta and progesterone levels in the ewe.
Polyvinyl catheters were placed in the maternal femoral artery (MA) and maternal uterine vein (UV) of 11 near-term ewes and in the umbilical vein of their fetuses. 1-5 days postoperatively 100 ml of air were injected into the umbilical vein of 7 fetuses. 4 fetuses served as controls. Samples of blood from MA were taken 15 min prior to air embolism and every 15 min for 3 h, then at +4, +5 and +6 h after air injection. Plasma levels of estrone (E1) estradiol (E2) and progesterone (P) were determined by radioimmunoassay. In MA and UV of treated ewes there was a significant decrease in P, but not in E1 or E2 after fetal death compared to control ewes. Control levels of P in MA were 9.6 ng/ml; values at 1, +2, +4 and +6 h were 8.8, 3.3, 2.3 and 1.2 ng/ml, respectively.
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Ovine placental cortisol production.
Cortisol levels were determined by radioimmunoassay in samples simultaneously obtained from the four vessels serving the ovine placenta (uterine artery and vein, umbilical artery and vein). These samples were collected daily over a 20- to 30-day interval in three animals in the latter third of pregnancy. Cortisol levels in the uterine and umbilical veins were higher than those in the arteries in 67 of 73 sample sets. Net synthesis of 11-deoxycortisol and cortisol from 17 alpha-hydroxyprogesterone by dispersed placental cells was also demonstrated in vitro. These data provide strong evidence that the ovine placenta has the ability to synthesize 11-deoxycortisol and cortisol in vitro and normally does so in vivo.
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Neuropathology in the chronic fetal lamb preparation: structure-function correlates under different environmental conditions.
In this study we examined the relationship between fetal metabolism, cardiovascular function, brain function, and eventual neuropathological outcome in the last third of gestation in the chronic fetal lamb preparation under a variety of environmental conditions. We concluded that the progressive hypoxia and metabolic acidosis secondary to acute placental insufficiency result in cerebral damage and functional deficit. Growth retardation and its attendant chronic hypoxemia, secondary to chronic placental insufficiency, do not have these results. However, intermittent interference with the umbilical circulation is associated with both functional and structural evidence of cerebral damage without systemic metabolic abnormality. The experimental, physiologic, and clinical implications of these observations are discussed.
Acidosis↗
Fetal metabolic response to experimental placental vascular damage.
The fetal metabolic response to repetitive placental damage, produced by microsphere embolization of the uteroplacental circulation, was examined longitudinally in eight singleton fetal lambs and compared with similar data from seven controls. Significant morphometric fetal growth retardation was associated with an abrupt cessation of the normal increases in oxygen, glucose, and lactate uptake observed in the control animals. However, fetal blood levels and umbilical substrate quotients did not change. At the time of sacrifice, fetal oxidative metabolic rate was reduced significantly. The significance of these findings relative to intact fetal survival is discussed.
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Disposition of methadone in the ovine maternal-fetal unit.
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Animals↗
Brain uptake of meperidine in the fetal lamb.
The uptake of meperidine by the brain of the fetal lamb was investigated by determining the concentration of meperidine in the fetal brachiocephalic artery and sagittal vein after intravenous and intramuscular administration to the mother. A positive arteriovenous gradient across the fetal brain existed for 10 minutes after intravenous administration, and for 20 to 25 minutes after intramuscular administration, thus indicating the uptake of meperidine by the fetal brain. The peak concentration of unbound meperidine in the fetal brain, as estimated from the plasma concentration of free meperidine at equilibrium, was three to four times greater after intravenous administration than after intramuscular administration. The findings suggest that, during labor, the route of administration of meperidine will determine the time course of meperidine in the fetal brain and, consequently, the time action of effects seen in the neonate. The lag time required for plasma-brain equilibration may explain the lack of correlation between the incidence of neonatal respiratory depression and the levels of meperidine in the cord after intramuscular administration.
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Umbilical blood flow response to embolization of the uterine circulation.
The uterine and umbilical blood flow response to uteroplacental insufficiency, produced by microsphere embolization of the uteroplacental circulation, was examined by means of electromagnetic flow transducers in 12 pregnant ewes. No acute changes were observed in either circulation immediately after embolization of the uterine vasculature. Significant morphometric fetal growth retardation, in terms of weight, length, and ponderal index, was not associated with early changes in fetal pH, PO2, or PCO2. However, the incremental increases in both flows that were observed in control animals did not occur either during or after embolization because of an increase in vascular resistance. During and after embolization the incremental increase in uterine blood flow was blunted or decreased in most, but not all, animals. A rapid, progressive, and persistent decrease in umbilical flow occurred in the growth-retarded group. The significance of these findings relative to intrauterine growth is discussed.
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Physiologic variability and fetal electrocortical activity.
The relationship between fetal electrocortical activity and multiple fetal parameters was examined in chronically instrumented fetal lambs. Consistent small but significant changes in fetal heart rate, mean arterial pressure, umbilical blood flow, and the cerebral uptake of glucose relative to oxygen were observed as fetal electrocortical activity cyclically shifted between high-voltage slow activity and low-voltage fast activity. Cardiovascular parameters were higher and the cerebral uptake of glucose relative to oxygen was lower during high-voltage slow activity than during low-voltage fast activity. The implication of these observations is discussed.
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Acute exercise stress in the pregnant ewe.
In the near-term pregnant ewe, acute treadmill exercise produced significant changes in maternal and fetal parameters only with the onset of maternal exhaustion which was unrelated to the degree or duration of maternal exercise. With exercise to exhaustion the rate of both uterine and umbilical blood flow fell but uterine and umbilical oxygen uptakes were unchanged. Although maternal lacticemia developed and fetal PO2 fell no excess lactate was produced by the uteroplacental tissues or fetus. The increase in maternal heart rate during exercise was directly related to the decrease in uterine blood flow.
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Renal tubular secretion of meperidine by the fetal lamb.
We have determined the renal clearance of meperidine and inulin simultaneously under steady-state conditions by using the chronic fetal lamb preparation. Meperidine was infused at a constant rate of 3.2 mg/min into the maternal vena cava, and [14C]inulin was infused at a constant rate of 0.22 muCi/min into the fetal vena cava. Total fetal urine output was collected for three consecutive 15-min intervals, and fetal blood was sampled at the midpoint of each urine collection. The mean meperidine clearance in 12 studies was 12.04 +/- 2.90 (S.E.) ml/min, whereas mean inulin clearance was 2.48 +/- 0.35 (S.E.) ml/min. In all but one animal, the ratio of meperidine clearance to inulin clearance is greater than one, indicating tubular secretion of meperidine. The results show that there is a negative relationship between meperidine clearance and urine pH, but there is no relationship between meperidine clearance and gestational age or urine flow rate. These results suggest that meperidine is secreted across the renal tubules by "ion trapping."
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Effect of epinephrine infusion on maternal and uterine oxygen uptake in the pregnant ewe.
Ten chronically instrumented pregnant ewes were studied to assess the effect of an epinephrine-induced decrease in uterine blood flow on the oxygen uptake of the uteroplacental-fetal tissue mass. Additional measurements of maternal cardiac output, oxygen uptake, arterial pressure, and hematocrit were obtained. Continuous systemic infusion of epinephrine at a rate of 0.3 to 0.4 microgram per kilogram per minute produced a mean decrease in uterine blood flow of 42 per cent (288 +/- 15 to 157 +/- 8 ml.per kilogram per minute). However, the oxygen uptake of the uteroplacental-fetal tissue mass remained at control levels due to an associated 79 per cent increase in the arteriovenous oxygen content difference across the uterine circulation. The calorigenic and cardiovascular systemic effects of epinephrine (a 22 per cent increase in maternal oxygen uptake and a 43 per cent increase in maternal cardiac output) were not related to the changes in either uterine flow or oxygen uptake. The implications of these observations are discussed.
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Urinary excretion of meperidine by the fetal lamb.
The renal excretion of meperidine by the fetus was determined in five chronic, unanesthesized fetal lamb preparations. Chronic indwelling catheters were implanted in the maternal aorta and vena cava, the fetal aorta, amniotic sac and allantoic sac. Via laparotomy, two catheters were implanted in the fetal bladder; the urachus and urethra were ligated. After intravenous administration of 2.5 mg/kg to the mother, meperidine rapidly appears in fetal urine. Approximately 0.02 to 0.05% of the maternal dose was excreted into fetal urine as unchanged meperidine in 300 min. The elimination half-life of meperidine in the fetus is 32.6 +/- 3.7 min when calculated from the urinary excretion rates, and 28.6 +/- 3.9 min when estimated from the plasma decay curve. The renal clearance of meperidine by the fetus ranged from 2.8 to 16.7 ml/min. Although the urachus and urethra were ligated, meperidine is found in samples of amniotic and allantoic fluid, indicating that the drug can diffuse across the placental membranes from the mother into these fluids. We have demonstrated that renal elimination of meperidine is a route of drug elimination by the fetus. These data support a pharmacokinetic model that describes the disposition of meperidine in the maternal-fetal unit by use of a two-compartment open model with elimination from both maternal and fetal compartments.
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The relationship between blood flow and oxygen uptake in the uterine and umbilical circulations.
Control measurements of uterine blood flow (N = 110) or umbilical blood flow (N = 84) and the oxygen content difference across the circulation in question were analyzed to assess the effect of flow rate, measured by the diffusion equilibrium technique, on the oxygen uptake of either the uteroplacental-fetal tissue mass or the fetus alone. Although the rate of uterine blood flow varied widely (110 to 418 ml. per kilogram per minute, the rate of uterine oxygen uptake did not change significantly at low or high rates of flow. Likewise, the rate of umbilical blood flow varied widely (154 to 444 ml. per kilogram per minute) without a significant change in fetal oxygen uptake at the extremes of flow. In both circulations this was due to the existence of a reciprocal relationship between flow rate and deltaO2.
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