Objective
We sought to determine if women with severe postpartum hemorrhage (PPH) secondary to uterine atony received greater amounts of oxytocin during labor compared to women without PPH.
Study Design
Subjects with severe PPH secondary to uterine atony, who received a blood transfusion, were compared to matched controls. Total oxytocin exposure was calculated as the area under the concentration curve (mU/min*min). Variables were compared using paired t test, χ 2 , and logistic regression.
Results
Women with severe PPH had a mean oxytocin area under the curve of 10,054 mU compared to 3762 mU in controls ( P < .001). After controlling for race, body mass index, admission hematocrit, induction status, magnesium therapy, and chorioamnionitis using logistic regression, oxytocin area under the curve continued to predict severe PPH.
Conclusion
Women with severe PPH secondary to uterine atony were exposed to significantly more oxytocin during labor compared to matched controls.
Postpartum hemorrhage (PPH) is a significant source of maternal morbidity and mortality and remains the most common cause of maternal death worldwide. In the United States, hemorrhage is second only to embolism as the most common cause of maternal mortality. From 1994 through 2006, the incidence in PPH in the United States increased 26%, with uterine atony accounting for the majority of this increase. Studies have described risk factors for PPH including prolonged third stage of labor, preeclampsia, episiotomy, history of PPH, multiple gestation, lacerations, augmented labor, second-stage arrest disorders, macrosomia, chorioamnionitis, general anesthesia, Hispanic ethnicity, and operative vaginal delivery. Clark et al found uterine atony to be the most frequent indication for emergency hysterectomy in their obstetric population, representing 43% of the cases. A recent multicenter study conducted by the Maternal-Fetal Medicine Unit Network of the Eunice Kennedy Shriver National Institute of Child Health and Human Development found that subjects with uterine atony following primary cesarean delivery were exposed to a longer duration of oxytocin compared to women without uterine atony. They also identified other associations with uterine atony including multiple gestation, maternal Hispanic race, birthweight >4500 g, and clinically diagnosed chorioamnionitis. Due to the strong association of oxytocin duration >12 hours in their study, the authors elected not to include this variable in the multivariable analysis for predictors of uterine atony. Therefore, it is unclear if this association would have held after controlling for the other independent risk factors. Regardless, prolonged oxytocin exposure is likely an important factor in the pathophysiology of uterine atony.
Oxytocin is a peptide that mediates its action through the oxytocin receptor (OXTR). The OXTR belongs to the family of G protein-coupled receptors (GPCRs), and like other GPCRs, undergoes rapid internalization in the setting of persistent agonist stimulation, which can limit the physiological actions of oxytocin. Prolonged oxytocin treatment leads to OXTR desensitization, thereby limiting further oxytocin-mediated contraction responses. Whether these molecular events lead to the clinical findings of dysfunctional labor patterns or uterine atony in the setting of prolonged oxytocin stimulation is unclear.
We conducted this case-control study to test the hypothesis that prolonged oxytocin exposure during labor increases the risk for PPH secondary to uterine atony.
Materials and Methods
Study design
This was a case-control study approved by the Duke University Medical Center Institutional Review Board (IRB) (IRB no. 6066-04-6ROER and IRB no. e00011058) and was conducted to test the hypothesis that women with severe PPH secondary to uterine atony received greater amounts of oxytocin compared to controls.
Study population
The medical records of women delivering at Duke University Medical Center over the 5-year period January 2000 through December 2004 with an International Classification of Diseases, Ninth Revision ( ICD-9 ) code for PPH were reviewed. Subjects with an ICD-9 for PPH were identified using the following codes: 666.0X (third-stage PPH), 666.1X (other immediate PPH), and 666.2X (delayed and secondary PPH). Next, the medical records for all women with an ICD-9 code for PPH were reviewed to find those who also received a blood transfusion. We then determined the etiology of PPH and defined cases in this study as women with severe PPH whose etiology for PPH was uterine atony. Next, a matched control was identified for each case. The controls selected were the next successive delivery following its paired case, matched for age (within 5 years), parity (nulliparous vs multiparous), and mode of delivery (vaginal, cesarean delivery before labor, cesarean delivery during labor).
Procedures
The medical records for cases and controls were reviewed by 1 of 3 physician study staff (C.A.G., M.J.P., L.N.C.J.). The study variables collected were subject’s age, race, height, weight, gravidity, parity, number of fetuses, gestational age at delivery, PPH with a previous delivery, type of delivery, need for induction, augmentation with oxytocin during labor, estimated blood loss at the time of delivery, prelabor hematocrit, first hematocrit following delivery, etiology of PPH (placental abruption, abnormal placentation, uterine atony, laceration), infant birthweight, maternal blood type, maternal medical conditions, type and quantity of blood product received, maximum maternal temperature during labor or postpartum (marker for chorioamnionitis or endometritis, respectively), and medications received or procedures conducted as treatment for PPH. Body mass index (BMI) was calculated based on the subject’s height and the first weight noted in her obstetric record. Change in hematocrit was calculated based on the difference between the hematocrit obtained at the time of admission and the lowest hematocrit obtained following delivery. At our institution, in the absence of hemorrhage, we routinely obtain a hematocrit on the morning following delivery.
Oxytocin exposure was calculated as the area under the curve (AUC). The time at which oxytocin infusion was initiated was recorded and the time and dose of each dose change was also noted. A graph of oxytocin dose (mU/min) vs time (minutes) was constructed for each subject. The area under the oxytocin dose curve (AUC, mU/min*min) for each subject was calculated using software (GraphPad Prism for Macintosh, version 5.0a; GraphPad Software, San Diego, CA). The time from oxytocin initiation to delivery, total time of oxytocin treatment, maximal oxytocin dose, time from maximal oxytocin dose to delivery, time from oxytocin discontinuation, and oxytocin dose at delivery were also recorded.
Statistical analysis
Continuous variables were compared between cases and matched controls using a paired t test and a paired Wilcoxon sign rank test. Categorical variables were compared using χ 2 or Fisher’s exact tests where appropriate. For the oxytocin characteristics (oxytocin AUC, time of oxytocin start to delivery, total time of oxytocin infusion, and oxytocin maximal dose) a value of 0 was entered for subjects not receiving oxytocin and the characteristics were compared using a paired t test and paired Wilcoxon signed rank test. Logistic regression models were constructed for the outcome severe PPH to identify potential confounding variables with odds ratio (OR) and 95% confidence interval. Significance for all analyses was defined as a P value < .05. All statistical analysis was conducted using software (JMP for Macintosh, version 8.0.1; SAS Institute Inc, Cary, NC).
Results
There were 12,476 deliveries at Duke University Medical Center over the 5-year period from January 2000 through December 2004. In all, 671 (5.4%) had an ICD-9 diagnosis of PPH. Of these 671 subjects, there were 109 deliveries to 109 unique subjects who required a blood transfusion and were, therefore, classified as subjects with severe PPH. Of these 109 subjects, the primary etiology of PPH was lacerations in 13%, retained products in 11%, placenta previa in 8%, and placenta accreta in 1%. In 54 subjects (50%) uterine atony was identified as the primary etiology of PPH.
As expected, the cases were similar to the controls with respect to maternal age and percent of subjects who were nulliparous. There was a trend toward lower BMI in the cases ( P = .054) and the cases were more likely to be of Hispanic ethnicity while the controls were more likely to be Caucasian or African American. Cases presented with a lower hematocrit at the time of admission (33.3% vs 35.6%; P < .001) compared to controls. There were no differences in other maternal characteristics including substance abuse, smoking, history of PPH, use of anticoagulation during the pregnancy, diabetes, chronic hypertension, or sickle cell trait between cases and controls ( Table 1 ).
| Characteristic | PPH atony (n = 54) | Control (n = 54) | P value b |
|---|---|---|---|
| Age, y a | 27.6 ± 7.3 | 27.2 ± 7.3 | .207 |
| Nulliparous, n (%) | 33 (61) | 33 (61) | NS |
| Body mass index, kg/m 2a | 29.9 ± 5.6 | 32.2 ± 6.8 | .054 |
| Race/ethnicity, n (%) | .010 | ||
| Caucasian | 14 (25.9) | 21 (40.4) | |
| African American | 15 (27.8) | 23 (44.2) | |
| Hispanic | 21 (38.9) | 6 (11.5) | |
| Asian | 2 (3.7) | 2 (3.7) | |
| Other | 2 (3.7) | 0 (0) | |
| Admission hematocrit, % a | 33.3 ± 4.0 | 35.6 ± 3.9 | < .001 |
| Substance abuse, n (%) | 1 (1.8) | 1 (1.8) | 1 |
| Smoking, n (%) | 6 (11.1) | 8 (14.8) | .567 |
| History of PPH, n (%) | 2 (3.7) | 1 (1.8) | .558 |
| Anticoagulation in pregnancy, n (%) | 2 (3.7) | 1 (1.8) | .558 |
| Diabetes, n (%) | 5 (9.3) | 1 (1.8) | .09 |
| Chronic hypertension, n (%) | 3 (5.6) | 2 (3.7) | .647 |
| Sickle cell trait, n (%) | 3 (5.7) | 1 (1.8) | .299 |
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