Obstetrics & Gynecology:
Prostaglandin E2 Analogue Sulprostone for Treatment of Atonic Postpartum Hemorrhage
Schmitz, Thomas MD, PhD; Tararbit, Karim MD, MPH; Dupont, Corinne PhD; Rudigoz, René-Charles MD; Bouvier-Colle, Marie-Hélène PhD; Deneux-Tharaux, Catherine MD, PhD; for the Pithagore6 group
From the Service de Gynécologie Obstétrique, Hôpital Robert Debré, AP-HP, the Université Paris Diderot, Inserm U953 Epidemiological Research Unit on Perinatal Health and Women's and Children's Health, and the Université Pierre et Marie Curie, Paris, France; and the Aurore Perinatal Network, Hôpital de la Croix Rousse, Hospices Civils de Lyon, Lyon, France.
*For a list of Pithagore6 group members who contributed to this study, see the Appendix online at http://links.lww.com/AOG/A247.
Funded by the French Ministry of Health under its Clinical Research Hospital Program (contract 27–35).
Corresponding author: Catherine Deneux-Tharaux, Inserm U953, Bâtiment de recherche, Hôpital Tenon, 4 rue de la Chine, 75020 Paris, France; e-mail: email@example.com.
Financial Disclosure The authors did not report any potential conflicts of interest.
OBJECTIVES: Use of prostaglandins, including sulprostone (an E2 analog), is recommended for second-line uterotonic treatment of atonic postpartum hemorrhage and might be considered as an indicator of quality of care in severe atonic postpartum hemorrhage management. Our objective was to estimate whether sulprostone was appropriately used and how it was tolerated in women with atonic postpartum hemorrhage.
METHODS: This large population-based study (146,781 deliveries) included 4,038 women with clinically assessed atonic postpartum hemorrhage in 106 French hospitals during 1 year. Severe postpartum hemorrhage was defined as one of the following: hemoglobin decline of 4 g/dL or more, transfusion, arterial embolization, surgical procedures, transfer to intensive care unit, or death. Sulprostone use in severe atonic postpartum hemorrhage was analyzed according to the mode of delivery and the characteristics of the maternity units.
RESULTS: Rates of sulprostone use were only 33.9% (n=1,370) and 53.5% (n=657) among women with atonic (n=4,038) and severe atonic (n=1,227) postpartum hemorrhage, respectively. In the latter population, sulprostone administration was less frequent after vaginal delivery than after cesarean delivery (45.6% compared with 86.5%, P<.01) in units performing fewer than 1,500 annual deliveries in public nonuniversity hospitals and in units where the obstetrician or anesthesiologist was not present 24 hours per day, 7 days per week. Fifty-one of the 1,370 women with sulprostone-treated atonic postpartum hemorrhage (3.7%, 95% confidence interval [CI] 2.7–4.7) experienced side effects, including seven (0.5%, 95% CI 0.2–1.0) with severe cardiovascular or respiratory symptoms that resolved when the hypovolemic shock was corrected and drug administration was stopped.
CONCLUSION: Sulprostone is underused for treating severe atonic postpartum hemorrhage after vaginal delivery, despite low rates of severe side effects in this population-based study.
LEVEL OF EVIDENCE: III
Postpartum hemorrhage is responsible for several maternal deaths and severe maternal morbid events in western countries.1–4 Uterine atony is the cause of the majority of cases. The management of atonic postpartum hemorrhage, besides monitoring, resuscitation, and transfusion procedures, generally follows a stepwise protocol in international5 and national guidelines.6–11 The first step consists of the administration of oxytocin or ergometrine, or both;5–11 if bleeding persists after these first-line oxytocic drugs, then prostaglandins are usually recommended;5–11 bleeding resistant to pharmacological treatments defines intractable postpartum hemorrhage and calls for invasive procedures,5–11 such as embolization or surgery.12–17 Although the first step of this strategy is widely accepted,18 few publications deal with prostaglandins as second-line treatment for postpartum hemorrhage aimed at avoiding these nonpharmacological third-line treatments.
Prostaglandins of three different classes have been proposed. Small retrospective studies first described the use of carboprost, a prostaglandin F2α analog,19,20 and sulprostone, a prostaglandin E2 analog,21,22 for persistent atonic postpartum hemorrhage in the late 1980s. In several countries, national clinical recommendations subsequently included these drugs,6–11 but no recent study has reported their actual use in current practices. More recently, the prostaglandin E1 analog misoprostol23,24 has been proposed, but a large randomized trial showed no benefit from its use as an adjunct to oxytocin in postpartum hemorrhage.25
The Dutch,9 German,10 and French11 guidelines recommend intravenous sulprostone in cases of persistent bleeding despite oxytocin treatment. In these countries, its use in severe atonic postpartum hemorrhage might be considered as an indicator of quality of care and analyzed as such to identify the characteristics of patients or of units possibly associated with suboptimal care. Assessing the actual translation of these recommendations into clinical practice appears all the more important given the usual limited effect of passive dissemination of guidelines.26 In addition, clinicians might be reluctant to use sulprostone because case reports have described an association between its use in women with postpartum hemorrhage and severe cardiovascular or respiratory events.27–29 This issue is controversial because no causal relationship has been documented and the actual frequency of these events is unknown.
In view of the reported increase in the rate of severe atonic postpartum hemorrhage in several developed countries,30 optimizing the use of second-line prostaglandins might help to reduce progression to severe postpartum hemorrhage and the need for invasive procedures. Our objectives were to assess the level and the determinants of the appropriate use of sulprostone and to estimate the frequency of severe associated side effects in a large, prospective, population-based cohort of women with postpartum hemorrhage in France.31
MATERIALS AND METHODS
The study population included women with postpartum hemorrhage selected from the Pithagore6 trial population.31The main features of the Pithagore6 trial have been provided in a previous article32 and are synthesized thereafter. It was a cluster-randomized controlled trial conducted in 106 French hospitals operating as six perinatal networks (the Perinat Centre network of the Centre region, the Port-Royal St. Vincent de Paul network in Paris, and the four networks of the Rhône-Alpes region). The main objective of this trial was to evaluate a multifaceted educational intervention for reducing the rate of severe postpartum hemorrhage. No significant difference in severe postpartum hemorrhage rate was found between the two groups of hospitals (details of this trial are available elsewhere31). The 106 Pithagore6 maternity units represented 17% of all French maternity units and covered 20% of national deliveries (n=146,781). Data were collected for 1 year in each unit from December 2004 through November 2006.
Postpartum hemorrhage was clinically assessed by the medical staff or biologically defined by a peripartum hemoglobin (Hb) decline of more than 2 g/dL (considered equivalent to the loss of more than 500 mL of blood), or both. Postpartum hemorrhage was clinically defined as a blood loss of more than 500 mL or as an excessive blood loss that motivated the performance of a manual removal of the placenta or an examination of the uterine cavity (or both). Prepartum Hb was collected as part of routine prenatal care during the last weeks of pregnancy; postpartum Hb was the lowest Hb level found in the 3 days after delivery. Birth attendants in each unit identified all deliveries with postpartum hemorrhage and reported them to the research team. In addition, a research assistant reviewed the delivery suite log book of each unit monthly and checked any available computerized patient charts. For every delivery with a mention of postpartum hemorrhage, examination of the uterine cavity, or manual removal of the placenta, the patient's obstetrics file was further checked to verify the postpartum hemorrhage diagnosis.
During the 2-year data collection period, 9,365 cases of postpartum hemorrhage (defined either clinically or by decline in Hb) occurred among 146,781 deliveries in the 106 Pithagore6 units for a total postpartum hemorrhage incidence of 6.4% of deliveries.
For this analysis, we first excluded cases of postpartum hemorrhage in which no excessive bleeding was clinically identified (n=2,705), that is, those diagnosed only by a decreased Hb level because, by definition, these cases did not receive any specific care for postpartum hemorrhage, and our objective was to study sulprostone use in postpartum hemorrhage and cases of postpartum hemorrhage not attributable to uterine atony according to the diagnosis mentioned in the medical files (n=2,622). The study population thus included 4,038 women with clinically assessed atonic postpartum hemorrhage.
In a second part of the analysis, we restricted the study population to cases of severe atonic postpartum hemorrhage. Severe postpartum hemorrhage was defined as a postpartum hemorrhage associated with one or more of the following: blood transfusion, arterial embolization, arterial ligation, other conservative uterine surgery, hysterectomy, transfer to intensive care unit, peripartum Hb decline of 4 g/dL or more (considered equivalent to the loss of 1,000 mL or more of blood), or maternal death. This group included 1,227 women. Figure 1 shows the selection process for these study groups. The Pithagore6 case report form was used to collect data from the chart of every delivery with confirmed postpartum hemorrhage, including the woman's characteristics and preexisting conditions, those of labor and delivery, and detailed procedures for postpartum hemorrhage management. These procedures were considered to have been performed only if they were specifically mentioned in the patient's chart. The time at which procedures were performed was collected as recorded in the medical files. A section of the data collection form focused on the use of sulprostone. In women who received this treatment, collected data included the dose and time of administration and the occurrence of symptoms potentially related to sulprostone side effects. The French guidelines recommend the use of continuous intravenous infusion of sulprostone not later than 30 minutes after postpartum hemorrhage diagnosis if bleeding persists despite oxytocin administration, and a dose that should not exceed 500 micrograms during the first hour and 1,500 micrograms in total.11 In women who did not receive sulprostone, the data collection form included questions regarding the reasons for nonuse, with one specific item regarding existing contraindications.
We first described the maternal characteristics of the 4,038 women with clinically assessed postpartum hemorrhage, ie, age, parity, number of fetuses, previous postpartum hemorrhage, onset of labor, mode and term of delivery, and administration of oxytocin to prevent postpartum hemorrhage. In this population, the frequency and the details of sulprostone administration were described, including the time between the postpartum hemorrhage diagnosis and the start of infusion (in minutes), the dose received during the first hour of treatment, and the total dose administered (in micrograms); these modalities of treatment were compared with the content of the French guidelines.11 Differences in these modalities according to mode of delivery were tested.
In women with atonic postpartum hemorrhage treated with sulprostone, other components of care were described, such as examination of uterine cavity, instrumental examination of the genital tract, administration of oxytocin, arterial embolization, conservative surgery, hysterectomy, and transfusion, with all studied as binary variables. Each postpartum hemorrhage was also characterized by the decrease in Hb (in g/dL) and the presence of a disseminated intravascular coagulation.
We analyzed the frequency of sulprostone use as an indicator of quality of care in women with severe atonic postpartum hemorrhage in which such treatment is expected. The prevalence of sulprostone treatment was described globally and then according to the route of delivery, ie, vaginal or cesarean; the characteristics of the status of the units, which were classified as university public, other public, and private; number of annual deliveries, categorized into less than 1,500, 1,500–2,499, or 2,500 or more; and 24-hour on-site presence of an obstetrician and an anesthesiologist. The same analyses were performed in the 788 women with severe atonic postpartum hemorrhage that lasted 30 minutes or more (duration of postpartum hemorrhage known in 899 [73.3%] of the 1,227 women with severe atonic postpartum hemorrhage).
Differences were tested with random-intercept multilevel regression models to take into account the clustering of the data; in addition, the intervention arm was introduced as a covariable in all models to adjust for any effect of the Pithagore6 intervention on the use of sulprostone. Finally, the frequency and type of reported side effects were described in all women with atonic postpartum hemorrhage treated with sulprostone.
The statistical analysis was performed with Stata10 software. The Sud Est III Institutional Review Board and the French Data Protection Authority approved the study.
During the study period, 4,038 women had clinical diagnoses of atonic postpartum hemorrhage. Among these patients, 18.2% were older than 35 years old, 48.5% were nulliparous women, 4.4% had multiple gestations, 5.7% had history of postpartum hemorrhage, 24.0% had induction of labor, 6.4% delivered before 37 weeks of gestation and 22.7% delivered after 41 weeks of gestation, 11.6% had cesarean deliveries, and 59.1% received prophylactic oxytocin. In this population, 1,370 (33.9%) women were treated with sulprostone (Fig. 1 and Table 1). Patients with atonic postpartum hemorrhage after cesarean delivery received sulprostone more frequently (80.1% compared with 27.9%, P<.01), sooner, and at a higher total dose (943±359 micrograms compared with 837±343 micrograms, P<.01) than women with atonic postpartum hemorrhage after vaginal delivery (Table 1).
In women treated with sulprostone for atonic postpartum hemorrhage, although mean Hb decrease and rates of Hb decrease of 4 g/dL or more did not differ significantly according to the mode of delivery, transfusion of red cells (20.3% compared with 33.1%, P<.01) and conservative surgery (2.1% compared with 10.7%, P<.01) were less frequent after vaginal delivery than after cesarean delivery (Table 2). Overall, 83.4% of the women treated with sulprostone for atonic postpartum hemorrhage did not require any additional procedures to control the bleeding; third-line procedures were more frequent after cesarean deliveries than after vaginal deliveries (26.1% compared with 13.0%, P<.01; Table 2).
Of the 1,227 women with severe atonic postpartum hemorrhage, 657 (53.5%) received sulprostone, and this proportion was also higher after cesarean delivery than after vaginal delivery (86.5% compared with 45.6%, P<.01; Fig. 1). In the women with severe atonic postpartum hemorrhage who did not receive sulprostone, two had a preexisting condition (asthma and arterial hypertension) that was the specified reason for nonuse. Sulprostone use to treat severe atonic postpartum hemorrhage was significantly less frequent in maternity units performing fewer than 1,500 deliveries per year, in public nonuniversity maternity units, and in maternity units where obstetricians or anesthesiologists were not present 24 hours per day, 7 days per week (Table 3). The overall heterogeneity between maternity units was mainly attributable to differences in sulprostone use after vaginal delivery. In severe atonic postpartum hemorrhage after cesarean delivery, units with different characteristics varied little in their use of sulprostone (Table 3). Analyses in women with severe atonic postpartum hemorrhage that lasted 30 minutes or more showed that 34.8% (274/788) did not receive sulprostone and provided similar results regarding differences by route of delivery and characteristics of units (data not shown).
Treatment-related side effects were reported in 51 (3.7%) patients treated with sulprostone for atonic postpartum hemorrhage (Table 4). Two thirds of these side effects were digestive. Seven women (0.5%) experienced severe side effects. Five women (0.3%) had severe cardiac side effects, although none had any history or risk factor for cardiovascular disease. The dose of sulprostone received did not exceed 500 micrograms during the first hour and 1,500 micrograms in total in any of these five women. One woman had tachycardia at 190 beats per minute that resolved spontaneously when drug administration stopped. Another had atypical chest pain, with normal cardiac markers and a normal electrocardiogram; the pain disappeared when plasma volume was expanded and drug administration was stopped. The other three women had signs of myocardial ischemia with elevated cardiac markers and abnormal electrocardiograms, all during severe postpartum hemorrhage with hypovolemic shock and the need for surgery (two hysterectomies and one arterial ligation). Two had twin deliveries. The coronary angiograms performed in two of these three women were normal. In these three women, symptoms resolved with symptomatic treatment of the hypovolemic shock and drug cessation. Finally, one women aged 40 or older experienced acute high blood pressure more than 200/110 mm Hg and one woman with asthma had acute cyanosis. These latter two cases were classified as severe side effects and also resolved when drug administration stopped.
Our study documents how sulprostone, a prostaglandin E2 analog recommended as a second-line uterotonic in postpartum hemorrhage,9–11 is actually used and tolerated in current clinical practice. Our results suggest that despite low rates of severe side effects, sulprostone is underused in atonic postpartum hemorrhage. Mode of delivery and organizational characteristics of maternity units were the main determinants of the adequacy of sulprostone use.
In this population-based study, two thirds of the women with atonic postpartum hemorrhage and almost half of those with severe atonic postpartum hemorrhage did not receive sulprostone. In accordance with our results, in the Scottish confidential audit of severe maternal morbidity, only two thirds of the patients with major postpartum hemorrhage (defined as an estimated blood loss of at least 2,500 mL, a transfusion of 5 or more units, or any treatment for coagulopathy) attributable to uterine atony did receive the prostaglandin analog carboprost,33 suggesting common French and Scottish difficulties in translating national guidelines into clinical practice. The use of prostaglandins is currently recommended in several sets of guidelines from high-resource countries.6–11 The stepwise management protocols that these guidelines recommend suggest that prostaglandin use in severe atonic postpartum hemorrhage can be considered as a marker of quality of care and can be used to assess the translation of postpartum hemorrhage-related guidelines into clinical practice. Our findings suggest that this management step can be improved. In most cases, the charts recorded no specific reason for the absence of treatment with prostaglandins and, thus, demonstrated a real gap between practice and guidelines.
Sulprostone was underused mainly in women who delivered vaginally, perhaps because postpartum hemorrhage and its severity are both more difficult to diagnose after vaginal delivery than after cesarean delivery. This hypothesis is supported, in our cohort, by both significantly longer times between diagnosis and initiation of sulprostone treatment and lower total sulprostone dose in women who delivered vaginally compared with those who had cesarean deliveries. An alternative and possibly complementary explanation is that within the group with severe postpartum hemorrhage, bleeding is actually more severe after cesarean delivery than after vaginal delivery, and therefore is more easily diagnosed as such, so that second-line uterotonics can be used more appropriately. This is suggested by the higher rates of transfusion, embolization, and surgical procedures in the cesarean delivery group. Conversely, management of severe atonic postpartum hemorrhage might be intrinsically more aggressive after cesarean delivery than after vaginal delivery because of the surgical context and sulprostone therefore might be prescribed more often. This hypothesis would explain the more frequent use of third-line procedures after cesarean deliveries compared with vaginal deliveries, even though postpartum hemorrhage severity, estimated by mean Hb decline or Hb decline of 4 g/dL or more, did not differ by mode of delivery.
The maternity unit's organizational characteristics also affected the adequacy of sulprostone use in women with severe atonic postpartum hemorrhage. Rates of sulprostone use were lowest in maternity units performing fewer than 1,500 annual deliveries, in public nonuniversity hospitals, and in units where obstetricians or anesthesiologists were not present 24 hours per day, 7 days per week. A study of risk factors for severe atonic postpartum hemorrhage in women with postpartum hemorrhage recently reported a similar relation with the organizational characteristics of maternity facilities.32 We hypothesize that treatment of persistent atonic postpartum hemorrhage may be inappropriate or delayed because of reduced human resources, ie, insufficient staff available for postpartum surveillance, especially after vaginal deliveries, in these units. Additionally, because most of these units offer delivery care only for low-risk pregnancies, their staff may be less familiar with the diagnosis and management of complications and with the logic of standardized care in such cases. Further educational interventions should focus on postpartum hemorrhage in the context of postpartum surveillance after vaginal delivery and should be directed specifically at small units and those dedicated to low-risk pregnancies.
Clinicians are frequently concerned that prostaglandin prescription in postpartum hemorrhage will induce severe cardiovascular or respiratory side effects as previously described with the use of both sulprostone27–29 and prostaglandin F2α analogs.34–36 Our results suggest, however, that severe cardiovascular or respiratory side effects are “uncommon” (ie, prevalence of 0.1%–1% according to the World Health Organization37). Underreporting of severe side effects, although always possible, appears unlikely for the following reasons: given the severity of the side effects and the close monitoring of women with postpartum hemorrhage, such events would not remain unnoticed or unreported in the files; in addition, concern regarding these possible side effects of sulprostone is common among clinicians, making them even more prone to report them; finally, clinical research assistants were trained to actively search for the related information in the medical files and report it in the specific section of the collection form. The causal role of sulprostone in the occurrence of these severe events remains uncertain. A retrospective study of 55 women with severe postpartum hemorrhage and hemorrhagic shock found laboratory signs of myocardial ischemia in 51% and electrocardiographic signs in 31%.38 In that study and in ours, a significant association between sulprostone administration and myocardial ischemia could not be evidenced. The three ischemic cardiovascular side effects reported herein all occurred in women in hemorrhagic shock, so it is difficult to disentangle the respective roles of a possible coronary spasm attributable to sulprostone and of the hemodynamic disorders. Conversely, because severe cardiovascular and respiratory side effects resolved when drug administration was stopped, some degree of causality cannot be ruled out. Finally, we note that the cases of severe cardiovascular or respiratory side effects reported in the literature with the use of sulprostone administered to control atonic postpartum hemorrhage were associated with route of administration that is not recommended (intravascular bolus),27 high combined doses of both sulprostone and dinoprost,28 or hemorrhagic shock.29 This comment is also relevant to the severe side effects reported after the use of prostaglandin F2α analogs.34–36 Therefore, severe side effects reported in sulprostone-treated women might be class-specific rather than drug-specific.
One limitation of our study is that data collection was retrospective and based on the content of medical files. However, although we cannot exclude the possibility that sulprostone administration was performed but not recorded in the medical files, this seems unlikely for such pharmacological treatment.
The design of this study had several strengths. It was population-based, covering all maternity units and, consequently, all deliveries in a given area. This ensures the external validity of its results, which may be extended to other populations of women with atonic postpartum hemorrhage in a similar context of care. The large number of women with postpartum hemorrhage treated with sulprostone provided good power to estimate the prevalence of severe and rare side effects, a power lacking in the size-limited retrospective studies published so far.
Our study shows that despite uncommon rates of potentially drug-related severe cardiovascular or respiratory side effects, sulprostone is underused in severe atonic postpartum hemorrhage. Our results should reassure obstetricians and encourage them to prescribe prostaglandins more often in this indication to control the uterine tone in accordance with national clinical guidelines. Second-line uterotonics in severe atonic postpartum hemorrhage may be used as an indicator of adequacy of care for postpartum hemorrhage. This step of postpartum hemorrhage management, especially after vaginal delivery, should be the focus of future educational interventions, particularly in units with less experience in complications of delivery.
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