Intravillous eicosanoid compartmentalization and regulation of placental blood flow.

OBJECTIVE: To determine the roles of the eicosanoids thromboxane and prostacyclin, and their compartmentalization, in the regulation of placental blood flow. METHODS: First, the sites of production of thromboxane and prostacyclin were determined within the placental villus using immunohistochemical staining for thromboxane and prostacyclin synthetase. Second, the production of both eicosanoids was studied in cultured trophoblasts and compared with that in the villous core by measuring the metabolites thromboxane B2 and 6-keto-prostaglandin F 1 alpha. Finally, eicosanoid production was assessed in intact villi after stimulation by an acute change in oxygen content, 5% to 95%. RESULTS: Immunohistochemical staining showed that thromboxane production was primarily within the trophoblasts, whereas prostacyclin production was localized to the endothelial cells within the villi. In culture, we found preferential production of prostacyclin by the villous core cells and increased production of thromboxane by trophoblasts. Perifusion of intact villi demonstrated increased production of thromboxane by trophoblasts in response to an increase in oxygen content. Prostacyclin levels were too low to be detected. CONCLUSIONS: Placental blood flow appears to be regulated by compartmentalized eicosanoids, with thromboxane affecting primarily the maternal side of the placental circulation and prostacyclin affecting primarily the fetal side.

Effects of low-dose aspirin therapy on plasma levels of polyunsaturated fatty acids: a preliminary investigation.

Polyunsaturated fatty acids play an important yet poorly understood role in pregnancy complications. We are interested in the effects of aspirin therapy on the metabolism of these compounds. To determine the effects of low-dose aspirin on plasma levels of polyunsaturated fatty acid precursors, we assayed linoleic, linolenic, arachidonic, eicosapentaenoic, and docosahexaenoic acids using high-performance liquid chromatography. Seventeen pregnant women being treated with aspirin therapy (81 mg/day) were evaluated between 9 and 37 weeks' gestation. Blood was drawn before initiation of aspirin therapy and after 3 or 4 days, and again after 3 or 4 weeks of therapy. We found no significant change in the plasma levels of fatty acids during aspirin therapy at either 3 or 4 days or 3 or 4 weeks compared with baseline. In this group of women with preexisting disease, low-dose aspirin does not appear to change the plasma levels of polyunsaturated fatty acid precursors of eicosanoids. Data on pregnant women without hypertensive disorders is needed to help in understanding the role and physiology of these important compounds.

Bacterial vaginosis in pregnancy: an approach for the 1990s.

It is proposed that clinicians screen all pregnant women at high risk for preterm labor and premature rupture of membranes for bacterial vaginosis, and treat all women when it is diagnosed. This infection is associated with a two to three times increase in preterm labor and delivery, premature rupture of the membranes, and endometritis. Although cause and effect have not been conclusively documented, these associations must be considered in the practice of obstetrics at the present. The paucity of vaginal Lactobacillus spp is pivotal in allowing overgrowth of many other organisms of the vagina. Screening is suggested because 50 percent of bacterial vaginosis is asymptomatic. The diagnosis, which is rapidly made and inexpensive, remains defined by clue cells seen on wet prep, high vaginal pH, and amine odor of the vaginal discharge. Optimal treatment of pregnant women with bacterial vaginosis is via oral or intravaginal metronidazole or clindamycin.

Ultrasound diagnosis of fetal anomalies associated with in utero cocaine exposure: further support for cocaine-induced vascular disruption teratogenesis.

The dramatic increase in cocaine use over the past decade has led to a concern about its possible teratogenicity. We have identified 6 structural fetal anomalies which we postulate may have cocaine-induced vascular accidents as the teratogenic mechanism: 2 complex choroid plexus cysts, gastroschisis, meconium peritonitis, urethral stenosis, and radial hypoplasia. Two additional anomalous neonates were born to perinatal cocaine users. Eight of 51 (15.7%) cocaine-exposed perinates exhibited anomalies versus 120 of 2,194 (5.4%) perinates without known cocaine exposure during this time period. This represents a 3-fold relative risk (RR = 2.87, OR = 3.22, chi square = 9.68, p < 0.005) for the cocaine-exposed fetus. Subjects were all identified as cocaine users prior to ultrasound-detected anomaly and ultrasonologists were blinded to maternal drug history. The vascular disruption model as the plausible mechanism for cocaine-associated teratogenesis is supported by the type of anomalies reported. In addition, cocaine use was prospectively determined to have occurred at the critical developmental period in each case.

A hemodynamic excitatory response to veratridine in the in utero lamb.

The inhibitory hemodynamic effects of the Bezold-Jarisch reflex in the adult animal, which play a role in the response to disease states, are elicited by veratridine and are mediated by vagal afferents. We tested whether the reported excitatory response to veratridine in the fetal animal may be caused by a maturational phase in the Bezold-Jarisch response. The effects of proprananol and atropine on the hemodynamic response to veratridine were examined at 124-141 d (mean, 133 d) of gestation in 11 fetal lambs instrumented long-term (instrumentation, 111-129 d of gestation). Seven lambs had intact vagal nerves, and four had bilateral cervical vagotomies. Veratridine injected into the superior vena cava (0.3 to 2.8 micrograms/kg) and the left atrium (0.2 to 0.8 microgram/kg) increased heart rate, arterial pressure, and left ventricular output, with the responses to left atrial injections occurring more rapidly. Propranolol markedly inhibited the increase in arterial pressure; atropine had no effect. Neither carbocaine, perfused around the cervical vagi, nor bilateral transection of the vagal nerves altered the hemodynamic excitatory response to veratridine. These findings demonstrate that the fetal excitatory response to veratridine is not mediated by vagal afferents, indicating the Bezold-Jarisch reflex does not undergo a maturational change from an excitatory reflex to an inhibitory one and suggesting the maturational loss of a sympathetically mediated hemodynamic reflex.

Decreased levels of polyunsaturated fatty acids in preeclampsia.

Plasma levels of polyunsaturated fatty acids in the n-3 and n-6 classes, which include linoleic, linolenic, arachidonic, eicosapentaenoic, and docosahexaenoic acids, were quantified with high-performance liquid chromatography in nonpregnant volunteers and in patients with normal pregnancies or preeclampsia at term. The total polyunsaturated fatty acid levels were not significantly different between nonpregnant and normal pregnant patients but was significantly lower in the preeclamptic patients compared with normal pregnant patients. This decreased level could represent altered fatty acid metabolism or altered storage and mobilization from lipid pools. Compared with nonpregnant patients, normal pregnant patients had significantly higher levels of eicosapentaenoic and docosahexaenoic acid. This may reflect normal physiologic changes in pregnancy, and the decreased level of eicosapentaenoic acid seen in preeclamptic patients may play a significant role in the pathophysiology of preeclampsia.

Sonographic measurements with umbilical and uterine artery Doppler analysis in suspected intrauterine growth retardation.

A retrospective analysis was performed to evaluate the role of sonographic measurement with umbilical and uterine artery Doppler studies in cases of suspected intrauterine growth retardation (IUGR). The sonogram was more sensitive (72%), but the umbilical artery Doppler scan was more specific (90%), for the diagnosis of IUGR. Abnormal uterine artery Doppler measurements in cases of IUGR diagnosed with a sonogram and umbilical artery Doppler scan were associated with chronic maternal hypertension. Those fetuses fared worse than those in which the uterine artery Doppler scans were normal. In contrast, small infants from pregnancies in which all three studies were normal performed well overall. Complementary use of these three studies to evaluate suspected IUGR fetuses may help us distinguish the small, troubled fetus from the small but healthy one.

The in utero left ventricle of the fetal sheep: the effects of isoprenaline.

1. Isoprenaline was infused into in utero fetal lambs to examine the effect of this beta-adrenoceptor agonist on left ventricular stroke volume and left ventricular output and test the generally held assumption that the fetal ventricle is markedly limited in its ability to increase ventricular output. 2. Seven in utero lambs (121-133 days of gestation) were instrumented with left ventricular dimension transducers, an ascending aortic electromagnetic flow transducer, a brachiocephalic arterial catheter and electrocardiographic and atrial pacing electrodes. 3. On the day of study, 5-8 days following surgery and 129-137 days of gestation, each lamb received infusions of isoprenaline, via the superior vena cava or left atrium, at rates which ranged from 0.005-0.5 microgram kg-1 min-1. 4. Heart rate and left ventricular stroke volume, output and end-diastolic and end-systolic dimensions were measured under control conditions and during various levels of isoprenaline infusion, with and without controlling heart rate. 5. Analysis of variance was done using the mean cell model. Least-square means and standard errors of the least-square means are reported. F ratios were calculated from type III sums-of-squares; P less than 0.05 was considered significant. 6. The mean heart rate increased with isoprenaline (P less than 0.0001) from a mean control level of 169 +/- 8 to 281 +/- 9 beats min-1 (+/- S.E.M.). 7. Mean left ventricular end-diastolic and end-systolic minor axis dimensions decreased significantly with isoprenaline from 16.7 +/- 0.1 mm (control) to 15.7 +/- 0.2 mm (P less than 0.0004) and from 11.7 +/- 0.1 mm (control) to 10.4 +/- 0.2 mm (P less than 0.0001) respectively. When heart rate was controlled with atrial pacing, mean end-diastolic dimension increased significantly at the higher isoprenaline doses from 14.6 +/- 0.1 mm (control) to 15.3 +/- 0.2 mm (control) (P = 0.0002), while mean end-systolic dimension fell significantly from 10.9 +/- 0.1 to 10.5 +/- 0.1 mm (P less than 0.003). Inasmuch as stroke volume increased, the increase in end-diastolic dimension and the fall in end-systolic dimension indicate an increase in venous return to the left ventricle. 8. During spontaneous rhythm, isoprenaline increased stroke volume from 2.45 +/- 0.06 ml (control) to 2.63 +/- 0.09 ml, not statistically significant. When heart rate was controlled, stroke volume increased with isoprenaline dose from 1.68 +/- 0.06 ml (control) to 2.40 +/- 0.08 ml (P less than 0.0001).(ABSTRACT TRUNCATED AT 400 WORDS)

Fetal umbilical artery Doppler response to graded maternal aerobic exercise and subsequent maternal mean arterial blood pressure: predictive value for pregnancy-induced hypertension.

Predictive tests for the identification of women at high risk of the development of preeclampsia are critical to allow the most appropriate preventive measures. Preeclampsia is a vasospastic condition of pregnancy characterized by early and enhanced vascular reactivity to endogenous pressor agents. Exercise tolerance testing with cycle ergometry to induce hemodynamic response measured with duplex Doppler A/B ratio of the umbilical artery could unmask latent vascular pressor hypersensitivity. Our prospective cohort study was designed to test the efficacy of the American College of Obstetricians and Gynecologists exercise in pregnancy guidelines for the low-risk athletic, physically active, or sedentary patient. The pattern of fetal response to material exercise testing at 28 weeks' gestation was compared with subsequent maternal mean arterial blood pressure and the development of pregnancy-induced hypertension and preeclampsia. Doppler A/B ratio during the recovery period was assessed as below baseline (18) or elevated above resting baseline values (12). Third-trimester blood pressure pattern was assessed to be elevated in 11 patients, 10 of whom had elevated recovery A/B ratios. The Fisher exact test results were (p = 0.00002) positive predictive value, 83%; negative predictive value, 94%; sensitivity, 91%; and specificity, 89%. Preeclampsia developed in four patients; all had elevated recovery A/B ratios. Fisher exact test results were (p = 0.01806) positive predictive value, 33%; negative predictive value, 100%; sensitivity, 100%; and specificity, 69%.

In utero cocaine exposure: observations of fetal behavioral state may predict neonatal outcome.

Components of fetal behavioral state organization reflect the successful integration of the central nervous system, have a specific developmental timetable, and can be studied with fetal ultrasonographic techniques. To test the hypothesis that evaluation of state organization is a marker of abnormal central nervous system maturation and a predictor of risk, we studied 20 fetuses and newborns exposed to cocaine in utero. Fetal assessments were accomplished by serial ultrasonographic examination, videotaped, and scored by a scheme developed by the authors to assess organization and regulation of behavioral states. Newborn neurobehavioral assessments also emphasized organization and regulation of behavioral state. Abnormal or delayed state behavior was identified in 13 of 20 fetuses. State organization was evaluated as suspect or abnormal for 16 of the 20 exposed newborns. Disorganized behavioral state in the fetus successfully predicted abnormal newborn behavior. These findings support the concepts that cocaine exposure disrupts central nervous system development and that fetal assessment of state is predictive of neonatal outcome.

Nonuniformity of fetal umbilical systolic/diastolic ratios as determined with duplex Doppler sonography.

Fetal umbilical arterial systolic/diastolic (S/D) ratios are said to be uniform throughout the umbilical cord. We evaluated this phenomenon by performing duplex Dopper on 73 fetuses at three sites in the umbilical cord: near the placental origin, in the free-floating midcord, and near the fetal abdominal wall insertion. Twenty-one of 73 fetuses examined (29%) demonstrated pronounced nonuniformity of the S/D ratios with a discrepancy of 1 or greater between any two S/D measurements. Studies demonstrated the highest S/D ratios at the fetal abdominal wall and lowest S/D ratios at the placental origin. These findings suggest that umbilical arterial flow velocity waveforms (FVWs) and S/D ratios are not uniform throughout the cord in all patients. The significance of this finding is uncertain; however, this variability in umbilical cord flow velocity waveforms stresses the importance of identifying the portion of the umbilical cord from which S/D ratios are obtained.

Normal sonographic appearance of the fetal neck late in the first trimester: the pseudomembrane.

A linear specular reflection simulating a membrane was visualized along the back of the neck on sonograms of ten normal fetuses ranging in age from 10 to 14 menstrual weeks. Follow-up ultrasound studies of eight of the fetuses and postpartum clinical examinations of all subjects were normal, revealing no evidence of neck abnormalities. Although this pseudomembrane is similar in appearance to published examples of early cystic hygroma, it is a normal finding that can be distinguished from early cystic hygroma on the basis of its less bulbous appearance and the absence of underlying septations. This structure corresponds in distribution to the skin along the back of the fetus and likely represents a specular reflection from the skin surface.

Immunohistochemical analysis of human uterine estrogen and progesterone receptors throughout the menstrual cycle.

Estrogen receptors (ER) and progesterone receptors (PgR) were studied immunohistochemically using specific antireceptor monoclonal antibodies in uterine tissue samples from 33 women in various stages of the menstrual cycle. Immunohistochemical localization was quantified as to intensity of staining and tissue distribution in glandular epithelium, stroma, and myometrium, and the results were compared with those of standard ligand binding assays. In all samples ER and PgR localized within the nuclei of target cells. The maximal concentrations of ER and PgR occurred in the mid- to late proliferative phase of the menstrual cycle. ER content declined throughout the secretory phase. In contrast, PgR content underwent unexpectedly complex and dyssynchronous fluctuations during the secretory phase of the menstrual cycle. Specifically, the glandular epithelium had diminished PgR content, while the stroma and myometrium maintained a significant PgR content. PgR and perhaps ER are not concordant in different cell types within the uterus. Segregation of function through alteration of receptor content may be an important mechanism in steroid-dependent growth and differentiation of target tissues.

A modified biophysical profile for antenatal fetal surveillance.

Three hundred thirty-seven high-risk pregnancies were screened using a modified biophysical profile consisting of nonstress testing (NST) and ultrasound evaluation of amniotic fluid volume. Ultrasound assessment of fetal breathing and body movements was performed only to evaluate the nonreactive NST. Decreased amniotic fluid volume and spontaneous fetal heart rate (FHR) decelerations were considered abnormal findings during antenatal testing, and served as indications for delivery regardless of FHR reactivity. Despite intervention, decreased amniotic fluid volume and spontaneous decelerations were associated with an increased incidence of meconium staining, decelerations during labor, cesarean section for fetal distress, and small for gestational age infants. Perinatal morbidity also occurred in patients with spontaneous decelerations and normal amniotic fluid volume. The search for spontaneous FHR decelerations by electronic fetal monitoring should continue during antepartum testing because FHR decelerations cannot be identified by conventional ultrasound assessment. The modified profile seems practical for routine assessment of fetal well-being in high-risk pregnancy, and affords insights unavailable with ultrasound surveillance alone.

Expectant management of partial placental abruption in previable pregnancies. A report of two cases.

Placental abruption is a major cause of perinatal morbidity and mortality, especially in the preterm infant. Two patients had previable pregnancies complicated by placental abruption and large extraamniotic hematomas. Precise diagnosis and follow-up with real-time ultrasound allowed expectant management until the delivery of viable infants became possible.

In utero right ventricular output in the fetal lamb: the effect of heart rate.

1. The effect of heart rate on right ventricular output was examined in six lambs during a period extending from 126 to 139 days of gestation. The fetuses had been surgically instrumented at least four days previously with a main pulmonary artery flow probe, right ventricular dimension transducers and left and right atrial pacing electrodes. 2. During spontaneous variations in heart rate, rate was correlated positively with right ventricular output (P less than 0.0001) and end-diastolic dimension (P less than 0.0001) among the lambs considered as a group, but no significant effect of rate on stroke volume was found. When individual responses were examined, output increased significantly with rate in sixteen out of seventeen observations. 3. With left atrial pacing, heart rate did not affect output. With right atrial pacing, rate correlated negatively with output (P less than 0.0001). With pacing from either site, rate correlated negatively with end-diastolic dimension (P less than 0.0001) and stroke volume (P less than 0.0001). 4. The introduction of a longer period interval during each pacing rate inhibited the rate-related decrease in dimension and allowed the ventricle to fill to the same end-diastolic dimension. The systole following these longer intervals had a greater stroke volume than did the preceding systoles with smaller end-diastolic dimension. The faster the preceding paced rate, the greater was the increase in stroke volume (P less than 0.001). 5. Right ventricular dimensions and volumes were measured in vitro, and the relationship was found to be linear using regression analysis. 6. This study demonstrates that experimentally induced variations in heart rate produce changes in end-diastolic volume and contractility which prominently affect right ventricular stroke volume. As a consequence, rate has, over a broad range, either no significant effect on output or a negative one. With spontaneous variations in rate, additional changes in contractility and venous return occur which affect stroke volume and end-diastolic volume and enhance right ventricular output. These relationships are similar to those in the adult heart, and demonstrate the absence of a maturational change in the effects of rate on ventricular function from the fetus to the adult.

Epiphyseal ossification centers in the assessment of fetal maturity: sonographic correlation with the amniocentesis lung profile.

The epiphyseal ossification centers of the distal femur (DFE) and proximal tibia (PTE) appear and enlarge during the third trimester of pregnancy. Late in the third trimester, the epiphysis of the proximal humerus (PHE) begins to ossify in some fetuses. Using the amniocentesis lung profile to determine the value of sonographic epiphyseal visualization as a predictor of pulmonary maturity, we studied 50 fetuses prospectively and compared the sonographic epiphyseal findings with results from the amniocentesis lung profiles. Nine fetuses with a visible PHE had a mature amniocentesis lung profile (accuracy of positive prediction = 100%), and then fetuses with an immature amniocentesis lung profile had no visible PHE (conegativity = 100%). Fetuses in which the combined DFE and PTE diameters were greater than 11 mm or in which the DFE and the PTE diameters were similar in size (DFE less than or equal to 1 mm larger than PTE) also yielded positive results. Copositivity and accuracy of prediction of an immature amniocentesis lung profile, on the other hand, were low (22%-25%) for the same epiphyseal parameters. These data suggest that antenatal visualization and measurement of the epiphyseal ossification centers of the fetal knee and shoulder may help to identify fetuses that would have a mature amniocentesis lung profile.

The effect of heart rate on in utero left ventricular output in the fetal sheep.

The effect of heart rate on left ventricular output was examined in seven fetal lambs at ages of 128 to 140 gestational days. The fetuses had been surgically instrumented at least 4 days previously with an ascending aortic flow probe, left ventricular dimension transducers, and left and right atrial pacing electrodes. Natural variations in heart rate of the lambs taken as a group correlated positively with left ventricular output, and negatively with ventricular end-diastolic dimension and stroke volume (P less than 0.0001). Rate did not affect output with right atrial pacing. With left atrial pacing, it correlated negatively with output (P less than 0.0001). At both pacing sites, rate correlated negatively with end-diastolic dimension and stroke volume (P less than 0.0001). The introduction of a longer interval during each pacing rate circumvented the rate-related changes in dimension and allowed the ventricle to fill to the same end-diastolic dimension. The systole at the end of the longer interval had a greater stroke volume than the preceding systoles. The faster the preceding paced rate, the greater was the stroke volume (P less than 0.0001). This study demonstrates that experimentally induced variations in heart rate produce changes in end-diastolic volume and contractility which prominently affect stroke volume. Over a broad range of rates, however, the effect of rate on left ventricular output is either negative or absent. With naturally occurring rate changes, there are additional changes in contractility and venous return which affect stroke volume. These combine to produce a positive relation between heart rate and left ventricular output. These effects of heart rate on output are qualitatively similar to those described for the adult animal.

Preinduction cervical ripening with prostaglandin E2 (Prepidil) gel.

The effect of preinduction cervical ripening with Prepidil, a commercially prepared prostaglandin E2 gel (0.5 mg), on the outcome of induction of labor with intravenous oxytocin was investigated. Fifty-nine pregnant women were randomized either to receive intracervical application of the gel or to undergo sham application. Compared to control subjects, patients in the group given Prepidil had significant increases in cervical Bishop scores, shorter induction-to-delivery intervals, lower maximum doses of oxytocin, and fewer days of induction. Systemic side effects were minimal, but 37% (11 of 30) of the gel-treated patients experienced labor prior to receiving oxytocin and 20% (six of 30) were actually delivered during the 12-hour ripening period. No differences in route of delivery or fetal outcome were found between the two groups.