During the first hours that follow the birth of a neonate (third and fourth stages of labor), complications are common and can threaten the mother's life. The most common complication is postpartum hemorrhage, which remains a leading cause of maternal mortality (25.0%), especially in developing countries.1 In developed countries, 3–5% of deliveries are complicated by postpartum hemorrhage; in developing countries, it is 50 times more common.2 Retained placenta is another complication of the third stage of labor. It occurs in 0.1–2% of deliveries3 and is associated with a high risk of hemorrhage. At present, treatment is by manual removal of the placenta, which requires an operating room, a surgeon, and an anesthetist, facilities that are often unavailable to women in resource-poor settings. As a result, this condition has a case fatality rate of nearly 10% in rural communities.3
The length of the third stage of labor and the possibility of associated complications depend on a combination of the ability of the uterine muscle to contract and the length of time it takes for placental separation. The principal management of the third stage of labor is aimed at reducing the time of delivery of the placenta, thereby minimizing serious adverse effects such as blood loss and retained placenta. Active management of the third stage of labor, which includes prophylactic injection of 10 international units oxytocin within 2 minutes of birth, early clamping of the umbilical cord, and controlled cord traction, is recommended by the World Health Organization for postpartum hemorrhage prevention.4
Umbilical vein oxytocin injection directs treatment to the placental bed and uterine wall, resulting in earlier uterine contraction and placental separation.5 However, limited published literature is available evaluating the effect of umbilical vein oxytocin injection in routine practices for active management of the third stage of labor. The purpose of this investigation was to estimate the effect of intraumbilical vein oxytocin injection in reducing blood loss during the third and fourth stages of labor, the length of the third stage of labor, and the incidence of manual removal of the retained placenta.
The present study was carried out at the Department of Obstetrics and Gynecology of the Bakirkoy Women's and Children's Teaching Hospital in Istanbul, Turkey, from January 2010 to March 2010. This tertiary teaching hospital has 14,000 deliveries annually. Ethical oversight was provided by the Bakirkoy Women's and Children's Teaching Hospital Ethics Committee (reference number 299). This trial was performed in compliance with the Declaration of Helsinki.
Inclusion criteria included no risk factors for postpartum hemorrhage, gestational age between 37 and 42 weeks, singleton pregnancy, live fetus, cephalic presentation, neonatal birth weight of 2,500–4,500 g, parity between one and five, maternal age younger than 35 years, and vaginal birth. Exclusion criteria included the following: blood pressure 140/90 mm Hg or greater, placenta previa, placental abruption, a history of any bleeding during pregnancy, a history of curettage, cesarean delivery or any uterine scar, a history of postpartum hemorrhage, hydramnios, signs or symptoms of maternal infection, known uterine anomalies, history of any drug use during labor, abnormal placentation (accreta, increta, or percreta), coagulation defects, instrumental deliveries, hemoglobin concentration less than 8 g/dL, history of anticoagulant drugs, β-mimetic medications during pregnancy, and prolongation of the first stage of labor longer than 15 hours.
After informed consent, simple randomization using a random number table was performed by the investigational pharmacy staff, who took no further part in the study. Infusion bags were prepared in accordance with randomization and labeled as bag A (oxytocin group), which contained 20 international units oxytocin diluted with 26 mL of saline, and bag B (placebo group), which contained 30 mL saline. Providers and patients were blinded to the contents of the bags until the conclusion of the study.
The medications (bag A or B) were injected directly in the umbilical vein after clamping. The injection was performed with a 30-mL syringe and an 18-gauge needle approximately 1–2 cm from the introitus. The solution was injected slowly over 1 minute, and at the end of the injection, the solution was milked toward the cord insertion.
Baseline characteristics of all participants were collected, including maternal age, parity, location of placenta (location of placental implantation was determined as anterior, posterior, or fundal by ultrasound examination), duration of first and second stages of labor, use of oxytocin during labor, and presence of episiotomy or laceration. In our unit, the third stage of labor (defined as the period of time from birth of the neonate until the delivery of the placenta) is managed by giving prophylactic oxytocin (Synpitan fort, 10 international units intramuscularly) at delivery of the anterior shoulder followed by early clamping of the umbilical cord. Placentas are delivered by controlled cord traction when signs of placental separation are observed. If the placenta was not spontaneously expelled, the length of the third stage of labor was calculated from delivery of the neonate until the placenta was manually removed. Placentas were manually extracted if they had not spontaneously delivered by 30 minutes after delivery of the neonate. After delivery, the vital signs and uterine tone of the patients were monitored as per routine protocol (blood pressure, pulse rate, and temperature were monitored every 15 minutes for 2 hours after delivery).
The primary outcome was the amount of blood loss in the third and fourth stages of labor. Other outcomes were duration of the third stage of labor, the percentage of placentas remaining undelivered beyond 15 minutes, the incidences of postpartum hemorrhage (500 mL or greater), severe postpartum hemorrhage (1,000 mL or greater), change in hemoglobin concentration, retained placenta, need for manual removal of the placenta, uterine curettage, need for additional uterotonic drugs (200 micrograms intravenous methylergometrine, 20 international units oxytocin infusion in 500 mL ringer lactate, 800 misoprostol rectally, or all), and side effects at the time of injection (anaphylactic reactions, hypotension, and cardiac arrhythmias).
The volume of blood loss was measured by weighing a sheet soaked from the end of the delivery to 2 hours after birth. Because it is important to collect the blood accurately, we used a specially designed operating sheet and an electronic scale to weigh all the material (with a 1-g deviation range). The quantity of blood (mL)=(weight of used materials−weight of materials before use)/1.05. Hemoglobin concentration was estimated on admission and 24 hours after delivery.6,7 The duration of the third stage of labor was defined as the time difference (in minutes) between delivery of the neonate and delivery of the placenta. The time interval was measured by the nurse attending the delivery and confirmed by the physician using a digital stop clock. The clock was started as soon as the neonate's body was totally delivered and stopped as soon as the placenta was completely expelled. Retained placenta was defined as a placenta that remained in the uterus for 30 minutes or more after delivery.
Sample size was calculated based on our prior experience at the center (unpublished data). The mean blood loss during the third and fourth stages of labor was approximately 250 mL (standard deviation 50 mL); a value of 250 mL blood loss was therefore chosen. To declare an equivalence of 25% with 80% power and a two-sided test of 5%, 197 patients were needed in each arm. An additional 10 patients were recruited to account for possible attrition.
The intention-to-treat analysis was carried out using the MedCalc 9.3 statistical software. Normal distribution of continuous variables was assessed using the Kolmogorov-Smirnov test; the χ2 test was used to analyze categorical variables; the Student's t test was used for the analysis of normally distributed continuous variables; and the Mann-Whitney U test was used for abnormally distributed variables. Relative risk with a 95% confidence interval (CI) was calculated. P<.05 was indicated statistical significance.
Of the 1,009 eligible women in early labor who were invited to participate, 560 were excluded and 449 were randomly assigned, 224 and 225 women to the placebo group and the oxytocin group, respectively. Nineteen women in the placebo group and 18 women in the oxytocin group did not enter the study after randomization because they no longer fulfilled the inclusion criteria. In total, 205 women in the placebo group and 207 in the oxytocin group were analyzed. The reasons for prerandomization and postrandomization exclusions are shown in Figure 1. Baseline demographic and clinical characteristics of patients were similar among the groups (Table 1).
The mean estimated blood loss and the proportion of women who experienced an estimated blood loss of more than 500 mL were significantly lower in the oxytocin group than the placebo group (195.3±81.0 mL compared with 288.3±134.1 mL, respectively; P<.001; and eight [3.9%] compared with one [0.5%], respectively; relative risk 1.84 95% CI 1.46–2.33; P=.02; Table 2). Significantly more women in the placebo group (seven [3.4%]) than in the oxytocin group (one [0.5%]) needed additional uterotonic agents; relative risk 1.78 95% CI 1.34–2.36; P=.03). In addition, two women in the placebo group experienced severe postpartum hemorrhage. Blood transfusion was required in only one patient, who was from the placebo group (P=.49).
The mean postpartum hemoglobin and hematocrit levels in the oxytocin group (10.0±1.4 g/dL and 31.8±2.3 g/dL, respectively) were higher than those of the placebo group (9.6±1.2 g/dL and 30.9±1.4 g/dL; P=.001 and P<.001, respectively).
The third stage of labor was significantly shorter in the oxytocin group than the placebo group (4.5±1.6 minutes compared with 7.9±3.4 minutes, respectively; P<.001). The percentages of placentas remaining undelivered beyond 15 minutes were 4.4% in the placebo group and 0% in the oxytocin group (P=.002). Retained placenta was seen in only one patient in the placebo group; it required manual removal and was resolved without any further intervention. No uterine inversions were observed. No adverse maternal outcome from injections was encountered during the study.
This randomized, double blind, placebo-controlled trial has shown that the use of intraumbilical injection of oxytocin with prophylactic injection of 10 international units oxytocin within 2 minutes of birth, early clamping of the umbilical cord, and controlled cord traction for active management of the third stage of labor reduced the average blood loss during the third and fourth stages of labor and the duration of the third stage. This finding is particularly significant for countries in which anemia, caused by either nutritional or environmental factors, is prevalent among pregnant women. In these cases, even a relatively small reduction of postpartum blood loss is clinically relevant. We kept vaginal blood loss during third and fourth stages of labor as a primary outcome. We have used an objective method of measuring blood loss rather than a subjective or clinical one (methods used in other studies). The amount of blood loss is a more meaningful and direct parameter to define postpartum hemorrhage than is hemoglobin estimation.
Several studies and systematic reviews have been published on the use of intraumbilical oxytocics, but these studies assessed the use of intraumbilical oxytocin for the treatment of retained placenta instead of postpartum hemorrhage.8–13 The recent National Institute for Health and Clinical Excellence (NICE) guidelines in the United Kingdom have recommended the use of umbilical oxytocin for the treatment of retained placenta.14 A few trials have investigated the routine use of intraumbilical oxytocin with active management of the third stage of labor.15–17 However, the findings of those trials are conflicting. From the existing evidence, it would appear that the routine use of intraumbilical oxytocin for the prevention of postpartum hemorrhage is questionable.
Ghulmiyyah et al15 randomly assigned 79 women to two groups: women assigned to the saline group received 30 mL normal saline in the umbilical vein, whereas those assigned to the oxytocin group had 20 international units oxytocin diluted in 30 mL saline injected directly in the umbilical vein. They found the mean drop in hemoglobin was significantly reduced in the oxytocin group (1.3 g/dL compared with 1.9 g/dL). However, they did not find a clinically significant reduction in the duration of the third stage of labor (5.9 compared with 7.8 minutes). They believe that this lack of difference may be the result of a type II error; the difference in the mean duration of the third stage of labor between the two groups was only 2 minutes, and their sample size was inadequate to show a difference in this outcome; the actual power of the study was only 60%. In contrast, Tehseen et al17 recently reported that the administration of 10 international units oxytocin to the intraumbilical vein along with intravenous administration of 5 international units oxytocin plus 0.5 mg ergometrine reduced average blood loss and the length of the third stage of labor. This disagreement may be related to differences in the infusion techniques used (amount of volume injected, dose of oxytocin used, or both) and to the sample size or study design.
In our study, the percentage of patients who experienced blood loss greater than 500 mL was higher in the placebo group than in the oxytocin group. Furthermore, more women in the placebo group required additional uterotonic agents. Our results showed that the oxytocin group had higher mean hemoglobin and hematocrit levels than the placebo group. In addition, the rate of placentas remaining undelivered beyond 15 minutes was lower in the oxytocin group. These findings are similar to that of Ghulmiyyah et al.15
What is the mechanism behind the possible reduced mean blood loss and duration of the third stage of labor with the use of intraumbilical vein injection of oxytocin? Oxytocin injected into the umbilical vein reaches the placental bed in relatively high concentrations. This stimulates uterine contractions, thus decreasing the area of the placental attachment site. The resulting tension causes the decidua spongiosa to give way with the formation of a hematoma. This accelerates the process of placental separation and expulsion, thus resulting in a shorter duration of the third stage of labor and a smaller amount of blood loss.18
Intraumbilical vein injections of 20 international units oxytocin over a short time period have potential adverse effects. These include an anaphylactic reaction, hypotension, and cardiac arrhythmias.15 No adverse side effects were seen in the present study.
The strengths of this study include its design as a randomized, double-blind, placebo-controlled trial. The a priori power was achieved, and the randomization scheme achieved its purpose of no differences between groups with regard to other variables. One limitation of the study is the relatively small sample size for looking at parameters such as retained placenta. For parameters such as retained placenta, it is important to have pooled data from various trials to reach a powerful conclusion. Another limitation of our study is exclusion of high-risk cases for postpartum hemorrhage.
In conclusion, the present study demonstrated that the use of intraumbilical injection of oxytocin with active management of the third stage of labor (prophylactic injection of 10 international units oxytocin within 2 minutes of birth, early clamping of the umbilical cord, and controlled cord traction) significantly reduced postpartum blood loss and the duration of the third stage. Larger studies involving high-risk populations and in low-risk populations in other institutions with different cesarean delivery rates and epidural anesthesia are necessary to confirm this finding.
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© 2010 by The American College of Obstetricians and Gynecologists.
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