Objective
The purpose of this study was to evaluate whether the use of oxytocin during the first and second stages of labor is associated with a higher incidence of postpartum hemorrhage (PPH) in pregnant women who received active management of third stage of labor (AMTSL).
Study Design
A secondary data analysis from vaginal deliveries in a hospital-based cohort study from 24 maternity hospitals in South America. The primary outcomes that were analyzed were moderate PPH (≥500 mL of blood loss), severe PPH (≥1000 mL of blood loss), and need of blood transfusion.
Results
A total of 11,323 vaginal deliveries were included. The incidence of moderate and severe PPH was 10.8% and 1.86%, respectively. Overall, 36% of deliveries received AMTSL. There was no association between induced/augmented labor and moderate PPH ( P = .753), severe PPH ( P = .273), and blood transfusion ( P = .603) in the population that received AMTSL.
Conclusion
AMTSL should be recommended, regardless of whether pregnant women received oxytocin during the first and second stages of labor.
Third stage of labor is defined as the period of time between the delivery of the baby and the delivery of the placenta. The length of this stage and its subsequent complications depend on a combination of the length of time it takes for placental separation and the ability of the uterine muscle to contract. There is strong evidence that the active management of the third stage of labor (AMTSL) reduces the risk of postpartum hemorrhage (PPH) by >40%. Currently, prestigious organizations such as the Joint Statement of the International Confederation of Midwifes, the International Federation of Gynecology and Obstetrics, and the World Health Organization recommend this practice for all vaginal deliveries as a way to prevent PPH in developed and developing countries.
AMTSL involves the administration of an oxytocic agent, early umbilical cord clamping and division, and controlled cord traction for delivery of the umbilical cord. Oxytocin is the current drug of choice for AMTSL. Because the binding of oxytocin to receptors on the myometrial cell membranes releases intracellular calcium and produces the uterine contractility, this drug is used as a potent stimulant of labor during early stages of labor. Oxytocin has been prescribed to induce labor from the beginning (induction of labor) or after the labor has been initiated and requires an oxytocic agent to improve uterine contractility (augmentation of labor). Therefore, because of current recommendations, many pregnant women who receive oxytocin during the third stage of labor are also exposed to the drug during the early stages of labor.
However, it has been observed that the use of oxytocin in first and second stages of labor that are associated with AMTSL may be associated with an increase in blood loss and blood transfusion. This finding may be product of an interaction between the use of oxytocin during 2 different stages of labor, which results in a decrease in the effect of AMTSL on PPH. Robinson et al showed that pretreatment with oxytocin resulted in a decrease in the percentage of cells that responded to subsequent oxytocin exposure. The authors found that this oxytocin-induced desensitization occurred over a clinical time-frame of 4.2 hours. Nevertheless, this potential interaction between oxytocin that is used during first and second stages and third stage of labor has not been described consistently.
The main objective of this current study was to evaluate whether the use of oxytocin during the first and second stages of labor is associated with a higher risk of PPH in pregnant women who received AMTSL. Our hypothesis is that patients who received oxytocin during the early stages of labor have a higher risk for PPH because of the presence of an interaction effect caused by the oxytocin-induced desensitization.
Materials and Methods
The Trial for Improving Perinatal Care in Latin America was a multicenter cluster randomized trial in 24 public maternity hospitals in Argentina and Uruguay. The main aim of the trial was to increase the use of 2 evidence-based birth practices: the use of oxytocin during the third stage of labor and selective episiotomy. For that purpose, the trial evaluated a behavioral intervention to facilitate the development and implementation of evidence-based clinical guidelines regarding the prevention of PPH and the use of episiotomy, compared with usual training activities.
A complete description of the trial and the main results have been published previously.
Of the 24 hospitals that were invited initially to participate in the study, 19 hospitals were finally randomized. For this secondary data analysis, we used baseline data from the 24 hospitals and postintervention data from the 19 randomized hospitals. The protocol for this analysis was approved by the Institutional Review Board from the Tulane Office of Human Research Protection.
Study population
A total of 15,263 deliveries were recorded in the final dataset. We excluded 3690 deliveries that were terminated by cesarean section delivery (24.2%), 14 cases whose birthweight was <500 g (defined as abortion), and 236 cases in which blood loss during the third stage of labor was not registered. After these exclusions, data were available from 11,323 women.
Clinical data collection instruments and database
Although the hospital was the unit of analysis at the end of the trial, individual patient information was collected at the patient level. A standard perinatal clinical history form was designed for the study in which data on obstetric history, prenatal care, labor, delivery, and neonatal outcomes were registered. These data were collected directly from the clinical records and the delivery log book from each hospital. For these analyses, we included all vaginal deliveries. Data for primary and secondary outcomes and on potential confounders or effect modifiers were collected.
Outcome measurement and definition
Nurses, midwives, and physicians who were part of the teams that attended deliveries at participating hospitals were trained in postpartum blood loss measurement. A plastic bag that had been designed to collect blood (drape) was used to collect postpartum blood lost. As soon as the baby was delivered, the drape was placed under the buttock. The blood was allowed to flow into the drape as long as the woman stayed in the delivery chair. After the blood was poured in a calibrated jar, the amount of blood was recorded on the study form, and the drape was disposed of properly. For the current study, we defined the primary outcome as moderate PPH based on the definition by the World Health Organization (≥500 mL of blood loss). In addition, severe PPH (≥1000 mL of blood loss) and the need of blood transfusion were used as secondary outcome measures.
Statistical analysis
All analyses were conducted in STATA software (version 9.0; Stata Corporation, College Station, TX). Delivery characteristics were calculated as means and proportions for continuous and categoric variables, respectively. Preliminary analyses included univariate and bivariate analyses. Chi-square statistics were used to determine whether the independent variable (use of oxytocin during early stages of labor) was associated significantly with PPH or blood transfusion. Two specific analyses were performed to evaluate our research question about the potential interaction between the use of oxytocin during the first and second stage of labor and the use of AMTSL with the same drug: (1) stratified analysis in women who received and who did not receive active management of third stage of labor and (2) multivariate analyses in the whole dataset with the use of interaction terms between induction/augmentation of labor and AMTSL. Because the included population was originally from 24 hospitals, we performed cluster regression analyses. Finally, sensitivity analyses were performed compared the final results of the 24 hospitals with (1) the 5 hospitals dropped after baseline collection and (2) the 19 hospitals kept in the main trial.
Power calculations
Based on (1) a minimum expected sample size of 2200 vaginal deliveries that received AMTSL (20% of all expected vaginal deliveries), (2) an estimated prevalence of moderate PPH of 6% (defined as blood loss ≥500 mL) in women who received active management of labor, and (3) a relative risk of 1.7 between exposure and nonexposure to oxytocin during early stages of labor, we estimated in advance that the power of the study would be 80% for the analyses when restricted to women who received AMTSL.
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