Oxytocin and the initiation of human parturition. IV. Plasma concentrations of oxytocin and 13,14-dihydro-15-keto-prostaglandin F2 alpha during induction of labor by artificial rupture of the membranes

The influence of artificial rupture of the membranes on plasma levels of 13,14-dihydro-15-keto-prostaglandin F2 alpha (PGFM) and oxytocin was examined in 23 pregnant women at term. Serial blood samples were collected before and 15 minutes, 2 hours, 5 hours, and 8 hours after artificial rupture of the membranes. A significant rise in the concentration of plasma PGFM was observed at 15 minutes in the majority of women (20 of 23), but the magnitude of this early rise or the lack thereof was not related to the subsequent course of labor. The concentration of plasma PGFM at 2 hours was, on the other hand, significantly correlated with the induction-delivery interval. Amniotomy, by itself, induced labor and delivery when the increased PGFM levels were maintained from 2 to 5 hours after the procedure (n = 16). In those cases where Pitocin stimulation was required for adequate uterine contractions, it was found that plasma PGFM levels had declined to initial values at 2 hours. Pitocin infusions then partially reversed this decline. In one patient, the cervix failed to dilate in spite of prolonged Pitocin infusion which did not induce significant uterine contractions, and the infusion did not reverse the marked fall in plasma PGFM after the early but transient rise. Mean plasma oxytocin levels did not rise significantly during labor induced by artificial rupture of the membranes and were, on the average, similar to the levels observed during the first stage of spontaneous or oxytocin-induced labor. Considering the previously demonstrated maximal levels of uterine oxytocin receptors in early labor, the absence of a rise in the plasma oxytocin levels does not negate a role for oxytocin in working synergistically with prostaglandins in the mechanism of labor.     

Oxytocin and initiation of human parturition. III. Plasma concentrations of oxytocin and 13,14-dihydro-15-keto-prostaglandin F2 alpha in spontaneous and oxytocin-induced labor at term

The plasma concentrations of oxytocin and 13,14-dihydro-15-keto-prostaglandin F2 alpha (PGFM) were measured in serial samples collected during the first stage of spontaneous and oxytocin-induced labor in 17 and 15 women, respectively. Four women in late pregnancy served as control subjects, with serial samples collected at similar intervals as during labor. During spontaneous labor, mean plasma oxytocin levels were consistently raised over the levels observed 1 to 2 weeks before the onset of labor and were higher than the levels in the control patients (mean, 19.9 +/- 3.1 pg/ml) and the initial levels in the oxytocin-induced group of women (mean, 17.4 +/- 4.8 pg/ml). The mean plasma oxytocin levels during spontaneous labor (45 +/- 3.9 pg/ml) were similar to those observed during infusion of 4 to 6 mU/min of synthetic oxytocin (49.1 +/- 10.9 pg/ml). Plasma oxytocin levels increased progressively with stepwise increments of the infusion. Plasma PGFM levels also rose during labor, but, in contrast to the oxytocin levels which increased in early labor, plasma PGFM levels did not increase significantly until relatively late in labor, provided the membranes were intact. The state of the membranes had a marked influence on plasma PGFM; patients with spontaneous rupture of membranes had significantly increased PGFM levels when admitted early in labor or when membranes ruptured during labor. This increase in prostaglandin F2 alpha (PGF2 alpha) production does not by itself suffice to initiate labor, as evidenced by the failure of premature rupture of the membranes to initiate labor in a number of patients with elevated PGFM levels in whom labor was then induced with oxytocin. Conversely, oxytocin induction was successful only when PGFM levels increased during the infusion of oxytocin; in the absence of a rise in plasma PGFM, oxytocin induction failed. These data add support to the view that both oxytocin and PGF2 alpha are required for adequate stimulation of the human uterus during labor. In addition, the data suggest that oxytocin rather than PGF2 alpha may be the major stimulus that initiates labor, whereas PGF2 alpha appears responsible for the progress of labor.     

Oxytocin receptors in the human uterus during pregnancy and parturition

We have determined the concentration and distribution of oxytocin receptors in myometrial and decidual tissues obtained at cesarean section or hysterectomy during pregnancy. Myometrial receptor concentration was low at 13 to 17 weeks but had risen about twelvefold by 37 to 41 weeks. After the onset of labor, either preterm or term, the receptor levels were maximal and significantly higher than before the onset of labor. In cases of failed induction of labor with oxytocin and in postterm pregnancies (43 to 46 weeks), the receptor concentration was significantly lower than in spontaneous labor. Myometrial receptor concentrations in the fundus and the corpus were similar and significantly higher than in the lower part of the uterine segment, and the cervix had the lowest concentration. The parietal decidua had oxytocin receptor concentrations of the same magnitude as the myometrium. These results are consistent with a functional role of endogenous oxytocin in the activation of the human uterus during pregnancy and parturition.     

Oxytocin for induction of labor

Oxytocin is the most common pharmacologic agent used for the induction and augmentation of labor. Oxytocin protocols can be divided into high-dose and low-dose protocols depending on the initial dose and the amount and rate of sequential increase in dose. Despite the frequency with which oxytocin in used in clinical practice, there is little consensus regarding which protocol is most appropriate. The purpose of this chapter is to review the most current data concerning recommendations for the use of oxytocin in the induction of labor, including cases of intrauterine fetal demise and vaginal birth after cesarean.     

Elective induction of labor conducted under lumbar epidural block. I. Labor induction by amniotomy and intravenous oxytocin.

Epidural analgesia (bupivacaine) was administered during labor after amniotomy, in some cases supplemented by intravenous oxytocin. A higher incidence of transient uterine hypertonus was seen after blocking. Fetal heart rate changes mainly took the form of bradycardia (in association with uterine hypertonus). At birth, the maternal biochemical condition was characterized by a lower degree of metabolic acidosis, compared to normal unanesthetized controls. The fetuses displayed a slight degree of hypoxia and hypercapnia. The mechanisms underlying these modifications are discussed. Epidural blockade in combination with elective induction of labor, whether or not supplemented by intravenous oxytocin, may carry a risk. Its magnitude is considered acceptable for both mother and fetus provided they are constantly under close surveillance, limited amounts of bupivacaine are administered and the second stage of labor is kept short. However, some warnings against epidural analgesia apply to patients with placental insufficiency and very active labor.     

Plasma oxytocin in initiation of labor

Serial radioimmunoassay measurements of plasma oxytocin (OT) in maternal venous blood have been carried out in 15 patients, during pregnancy, labor, and delivery. Fetal plasma OT was also measured in the blood from the umbilical vein and umbilical artery. The results indicate that: (1) during pregnancy, plasma OT is present in maternal blood; (2) the quantity of plasma OT increases with advancing pregnancy; (3) no OT surge occurs around the onset of labor; (4) the plasma OT surge occurs with cervical dilatation and vaginal distention. The data indicate that OT does not play a primary role in the initiation of labor and support the concept that OT most likely contributes to formation of prostaglandins through the uterine contractions OT produces. OT surges, frequently called spikes, have been observed to occur during pregnancy as well as during labor. During the course of labor, OT surges have been encountered in association with rupture of the membranes, vaginal examination, and descent of the vertex, and have occurred almost consistently with maximal cervical and vaginal distention. Such OT surge was suppressed by effective spinal and pelvic regional anesthesia. Therefore, this surge is consistent with the Ferguson reflex described in experimental animals, and it represents the first evidence that the Ferguson reflex, in fact, exists in human beings. Evidence is presented here that an excess of OT in fetal blood over that found in maternal plasma was associated with hypertonic, irregular, tumultuous or prolonged labor and with mild to moderate fetal hypoxia and fetal distress peculiar to abnormal uterine contractions.     

Oxytocin augmentation of dysfunctional labor. V. An alternative oxytocin regimen

A regimen is described in which the time from the start of a large dose of oxytocin to a myometrial response was used for selection of a maintenance dose. The method is based on our experience that continuous intravenous doses of oxytocin in the therapeutic range for the augmentation of labor require about 40 minutes of intravenous infusion to achieve a steady-state plasma concentration of oxytocin. The method effectively identified the proper maintenance dose on the first attempt in 43 of 59 patients (73%) and on the second in 58 of 59. The doses selected effected cervical dilatation in 55 of 59 cases (93%). Comparison of the timed dose method with an arithmetic progression regimen revealed the former method to select the minimum effective dose more rapidly, but that method had no advantage in shortening the time from the start of oxytocin to complete cervical dilatation. Examination of the plasma concentration of oxytocin by radioimmunoassay demonstrates that the maintenance dose selected by the duration of the interval from the start of infusion to a myometrial response sustains the plasma oxytocin concentration obtained by the initial dose. These data lend additional evidence that any particular dose of oxytocin in the therapeutic range requires approximately 40 minutes to achieve a steady-state plasma concentration.     

Plasma oxytocin in human pregnancy and parturition

Oxytocin concentrations were determined in serial peripheral plasma samples collected from clinically normal women during pregnancy and labor. Measurable concentrations of this hormone were detected in all maternal plasma samples during pregnancy, but there were wide differences in values between patients. Serial samples from individual patients revealed a pattern of gradual rise of oxytocin levels with advancing gestation and the increase in concentration was statistically significant. There were no significant differences in oxytocin levels at any stage of labor, with or without epidural analgesia. Oxytocin levels at the onset of the second stage did not differ statistically from those at crowning. Comparison of cross-sectional data showed no significant difference between the mean oxytocin concentration in early labor and in late pregnancy. Oxytocin surges occurred, but not in a regular pattern. Plasma oxytocin concentration did not increase after pelvic examination, sweeping of the membranes, low amniotomy or after cervical vibration. After spontaneous vaginal delivery, umbilical arterial plasma levels of oxytocin were consistently higher than plasma concentrations from the umbilical vein. The fetal arterio-venous difference was less pronounced at elective cesarean section. At spontaneous vaginal delivery, with and without epidural anesthesia, plasma levels from the umbilical artery were significantly higher than the maternal levels. After vaginal delivery, oxytocin levels in cord plasma were significantly higher than at elective abdominal delivery. Some methodological aspects with regard to blood sampling and to plasma oxytocin radioimmunoassay procedures are discussed. From the results presented it is concluded that the human fetus can be an important source of oxytocin and that neurohumoral birth reflexes described in animals do not occur systematically in man.     

Fetal and maternal oxytocin in human parturition

Measurements of oxytocin in maternal and fetal circulation during human labor are reviewed and related to known changes in uterine oxytocin sensitivity during pregnancy and labor. It is concluded that oxytocin is secreted in short-lasting spurts; therefore levels measured with infrequent intervals do not give adequate information on the amounts of oxytocin secreted during labor. Presently, there is little evidence for an increased maternal secretion rate of oxytocin at the onset of labor, but during labor a progressive increase occurs, with a maximum at the expulsive phase. Fetal secretion rate also increases markedly during labor, but the timing of this increase is still unknown. The dramatic increase in human uterine oxytocin receptors at term makes the uterus responsive to very small amounts of oxytocin. Hence, an increased oxytocin secretion rate is not a necessary prerequisite for oxytocin-stimulated contractions during labor. Evidence from oxytocin receptor blockade and suppression of oxytocin secretion supports the concept that oxytocin is an important stimulus for uterine contractions in early human labor.     

Factors implicated in the initiation of human parturition in term and preterm labor: a review

Abstract

After accommodating the pregnancy for an average of 40 weeks, the uterus expels the fetus, the placenta and the membranes through the birth canal in a process named parturition. The absolute sequence of events that trigger and sustain human parturition are not yet fully clarified. Evidence suggests that spontaneous preterm and term labor seem to share a common inflammatory pathway. However, there are several other factors being involved in the initiation of human parturition. Placental corticotropin releasing hormone production seems to serve as a placental clock that might be set to ring earlier or later determining the duration of pregnancy and timing of labor. Estrogens do not cause contractions but their properties seem to capacitate uterus to coordinate and enhance contractions. Cytokines, prostaglandins, nitric oxide and steroids seem also to induce ripening by mediating remodeling of the extracellular matrix and collagen. Infection and microbe invasion resulting in chorioamnionitis also represents a common cause of early preterm labour. This review provides an overview of all these factors considered to be implicated in the initiation of human parturition.