Brian Kirshon

Indomethacin in the treatment of premature labor. Effects on the fetal ductus arteriosus.

Indomethacin is a potent agent in the treatment of premature labor, but its use has been limited because of concern about its constrictive effects on the fetal ductus arteriosus. To study these effects we used serial fetal echocardiography in 13 pregnant women in premature labor who received indomethacin according to three different dose schedules, ranging from 100 to 175 mg per day, for a maximum of 72 hours. The gestational ages of the fetuses ranged from 26.5 to 31.0 weeks. The detection of ductal constriction in 7 of the 14 fetuses by echocardiography led to the discontinuation of indomethacin. Three fetuses also had tricuspid regurgitation. There was no statistically significant difference between the mean (+/- SEM) gestational age of the fetuses with ductal constriction and that of those without constriction (29.3 +/- 0.59 and 28.4 +/- 0.52, respectively). There was no relation between serum indomethacin levels in the mothers and ductal constriction. In all seven fetuses affected, ductal constriction had resolved by the time they were restudied 24 hours after the discontinuation of indomethacin. Persistent fetal circulation was not detected in any of the 11 neonates studied after delivery. Indomethacin used to treat premature labor appears to cause transient constriction of the ductus arteriosus in some fetuses, even after short-term use.

Effects of physiologic load of pregnancy on left ventricular contractility and remodeling

Left ventricular (LV) adaptation to the hemodynamic load of pregnancy has been studied with load-sensitive ejection-phase indexes, but the results of these studies are conflicting. The aim of this study was to examine the effects of the hemodynamic load of pregnancy on the contractile state of the left ventricle by using load-adjusted indexes of contractility. Thirty-four healthy women were prospectively studied by serial echo and Doppler examinations at six periods during pregnancy and after delivery. LV volume increased 10.5%, paralleling the change in stroke volume. End-systolic stress, an index of myocardial afterload, decreased 28.8% because of a decrease in end-systolic pressure and an increase in LV thickness/diameter ratio. Despite the increase in preload and the decrease in afterload, ejection phase indexes did not change during or after pregnancy. Although remaining within the normal range, the afterload-adjusted velocity of circumferential fiber shortening, an index of contractility that is relatively insensitive to preload, transiently decreased by 1.75 SDs during gestation, returning to non-pregnant values 2 to 4 weeks postpartum. Thus the increase in hemodynamic load that characterizes normal pregnancy is associated with preservation of global pump function. The transient decrease in contractile state may represent an adaptation phase of the contractile elements of the myocardium to the rapid changes in loading conditions observed during the first trimester of pregnancy.

Placental transfer of indomethacin in the human pregnancy

Little is known about the placental transfer of indomethacin in the human pregnancy. Twenty-six pregnant patients (gestational age, 29.4 +/- 0.5 weeks) were given a 50 mg oral dose of indomethacin 6.08 +/- 0.07 hours before 42 cordocenteses undertaken for standard indications. Maternal serum, fetal serum, and amniotic fluid levels were measured at the time of each procedure. Maternal indomethacin levels were not significantly different from corresponding fetal levels (218 +/- 21 vs 219 +/- 13 ng/ml). The maternal/fetal serum ratio (0.97 +/- 0.07) was not found to vary with gestational age (R = -0.07, p = 0.66). Fetal serum levels were significantly higher than corresponding amniotic fluid levels (219 +/- 16 vs. 21 +/- 2 ng/ml; p less than 0.001). The fetal/amniotic fluid ratio (10.0 +/- 1.2) did not vary with gestational age (R = 0.33, p = 0.11). Indomethacin crosses the human placenta easily throughout gestation; only small amounts of the unchanged drug are found in the amniotic fluid.

Doppler assessment of the fetal and uteroplacental circulation during nifedipine therapy for preterm labor

To investigate the effects of nifedipine on the human fetal circulation, 11 fetuses whose mothers were treated with nifedipine for treatment of preterm labor were studied. Maximum velocity waveforms were obtained in the middle cerebral artery ( n = 8), renal artery ( n = 6), ductus arteriosus ( n = 8), and umbilical artery ( n = 10). Transvalvular maximal velocity waveforms were obtained across the aortic ( n = 11) and pulmonary ( n = 7) valves. Maternal uterine arteries also were studied ( n = 7). Doppler data were collected before and 5 hours after nifedipine therapy. Patients received an oral loading dose of 30 mg of nifedipine followed by a second oral dose of 20 mg 4 hours later. No significant difference in the flow velocity waveforms was found in the vessels studied 5 hours after the initial dose. These results suggest that short-term nifedipine therapy does not influence either fetal or uteroplacental circulation as evaluated with the Doppler technique.

Effects of maternal aerobic fitness on cardiorespiratory responses to exercise.

We hypothesized that aerobically fit women who continued to exercise throughout pregnancy would have enhanced cardiorespiratory responses to exercise. Physically active (N = 10) and sedentary (N = 6) subjects were compared during steady-state (15 min) semi-recumbent cycle exercise performed at a given heart rate (HR; 140 b.min-1) twice during pregnancy (25 wk, 36 wk) and 12 wk postpartum. Indirect calorimetry was used to measure volumes and fractional concentrations of expired gases. Cardiac output was estimated via CO2 rebreathing. Data were analyzed with repeated measures ANOVA. Caloric expenditure during exercise was significantly (P < 0.001) greater in the physically active (7.2 kcal.min-1) compared with sedentary (4.7 kcal.min-1) subjects. Alveolar ventilation and cardiac output responses to exercise were proportionally greater (P < 0.001) in the aerobically fit subjects. Ventilatory equivalents for O2 and physiological dead space/tidal volume ratios were significantly (P < 0.01) lower in the physically active subjects during exercise. In contrast, ratings of perceived exertion during exercise did not differ between subject groups. It appears that a physically active womans enhanced cardiorespiratory responses to acute exercise are maintained during pregnancy if she continues her aerobic fitness program throughout gestation.

Nimodipine in the management of preeclampsia: Maternal and fetal effects

OBJECTIVE Our purpose was to determine the effects of orally administered nimodipine on selected maternal and fetal parameters in patients with preeclampsia. STUDY DESIGN Ten consecutive patients were given 30 mg of nimodipine orally every 4 hours from admission until 24 hours after delivery. Maternal and fetal cerebral blood velocity, umbilical artery blood velocity, fetal heart rate variability, maternal blood pressure and heart rate, and transplacental passage of the drug were studied. All 10 patients were delivered within 24 hours of the first dose of nimodipine. RESULTS There was an acute and significant reduction in the pulsatility index in the smaller diameter maternal cerebral arteries (ophthalmic and central retinal) and in the fetal middle cerebral artery. The umbilical artery systolic/diastolic ratio was also significantly reduced. Maternal blood pressure was controlled without the need for other antihypertensive medication, and although there was an increase in heart rate after administration of the drug, it was well tolerated. Nimodipine reached significant maternal and fetal levels within 2 hours. CONCLUSIONS Nimodipine is rapidly absorbed after oral administration and has significant maternal and fetal cerebral vasodilator activity. It is an effective, easily administered antihypertensive agent when used in patients with preeclampsia.

Amniotic fluid glucose and intraamniotic infection

Thirty-nine patients with either premature labor and/or preterm premature ruptured membranes underwent transabdominal amniocentesis to enable the following amniotic fluid analyses to be performed: culture and sensitivity, Grams stain, and glucose determination. All nine patients with intraamniotic infection had amniotic fluid glucose values less than 10 mg/dl. Three patients with amniotic fluid glucose levels less than 10 mg/dl but without chorioamnionitis were delivered of infants within 72 hours of admission. The mean amniotic fluid glucose level of patients with intraamniotic infection (5 +/- 2.4 mg/dl) was significantly lower than in those without intraamniotic infection (39.8 +/- 18.42 mg/dl). All patients with amniotic fluid glucose values less than 10 mg/dl had either bacteria and/or white blood cells on Grams stain. Two patients without chorioamnionitis had white cells on Grams stain and amniotic fluid glucose values greater than 10 mg/dl. It appears that amniotic fluid glucose is more sensitive and more specific than Grams stain in the diagnosis of intraamniotic infection. All 12 patients with low amniotic fluid glucose values were delivered of infants within 72 hours as the result of either the presence of infection or the progression of labor.

Flow velocity waveforms of the vascular system in the anemic fetus before and after intravascular transfusion for severe red blood cell alloimmunization

Sixteen intravascular transfusions were performed in 16 anemic human fetuses. To investigate the status of the vascular system with Doppler ultrasonography before and after correction of anemia, pulsatility index values were obtained for the flow velocity waveforms of the middle cerebral artery, internal carotid artery, anterior cerebral artery, thoracic aorta, abdominal aorta, renal artery, femoral artery, and umbilical artery before and the day after the correction of anemia. The fetuses were divided into two groups: (1) fetuses with a hematocrit level between 2 and 4 SDs below the normal mean value for gestational age and (2) fetuses with a hematocrit value less than 4 SDs below the normal mean value for gestational age. No significant differences were observed in the pulsatility index values of the vessels studied before and after correction of anemia in both groups of fetuses. These data suggest that the pulsatility index cannot be used as an indicator of fetal anemia at the hematocrit values studied.

Effects of low-dose dopamine therapy in the oliguric patient with preeclampsia

Central hemodynamic and renal responses to low-dose dopamine (1 to 5 micrograms/kg/min) infusion were studied in six oliguric (less than 0.5 ml/kg/hr) patients with severe preeclampsia. Hemodynamic parameters were measured and renal function tests were done before and during therapy. There was a significant rise in urine output from a mean (+/- SD) of 21 +/- 10 to 43 +/- 23 ml/hr, accompanied by a rise in cardiac output from 6.8 +/- 1.8 to 8.0 +/- 2.3 L/min (p less than or equal to 0.05). There were no significant changes in blood pressure, central venous pressure, or pulmonary capillary wedge pressure. The fractional excretion of sodium, negative free water clearance, and osmolar clearance tended to rise during dopamine therapy. No adverse maternal or fetal effects occurred. We conclude that low-dose dopamine produces a significant increase in urine production with resolution of oliguria in severe preeclampsia.

Unknown uterine scar and trial of labor.

A review of 393 patients undergoing trial of labor after one or more previous cesarean sections was performed. Three hundred patients had an unknown uterine scar, 88 patients had a documented low cervical transverse incision, and five patients had a prior low vertical incision. The rate of vaginal delivery and maternal and fetal morbidity was no different in those patients with an unknown prior uterine incision compared with those having a known prior low cervical transverse incision. In 66 of the patients with a documented low cervical transverse incision, the original operative record was reviewed in regard to single-layer closure of the uterine incision versus double-layer closure or imbricating technique. No patient with a double-layer uterine closure had a subsequent dehiscence, whereas three patients with a prior single-layer closure exhibited scar separation. These data suggest that neither an unknown scar nor a single-layer uterine closure places the mother or fetus at greater risk.