Objective
The purpose of this study was to examine the risks of acute coronary syndrome (ACS) and acute myocardial infarction (AMI) that are associated with methylergonovine maleate (Methergine; Novartis Pharmaceuticals Corporation, Plantation, FL) use in a large database of inpatient delivery admissions in the United States.
Study Design
We conducted a retrospective cohort study using data from the Premier Perspective Database and identified 2,233,630 women who were hospitalized for delivery between 2007 and 2011 (approximately one-seventh of all US deliveries during this period). Exposure was defined by a charge code for methylergonovine during the delivery hospitalization. Study outcomes included ACS and AMI. Propensity score matching was used to address potential confounding.
Results
Methylergonovine was administered to 139,617 patients (6.3%). Overall, 6 patients (0.004%) who were exposed to methylergonovine and 52 patients (0.002%) who were not exposed to methylergonovine had an ACS. Four patients (0.003%) who were exposed to methylergonovine and 44 patients (0.002%) in the not-exposed group had an AMI. After propensity score matching, the relative risk for ACS that was associated with methylergonovine exposure was 1.67 (95% confidence interval [CI], 0.40–6.97), and the risk difference was 1.44 per 100,000 patients (95% CI, –2.56 to 5.45); the relative risk for AMI that was associated with methylergonovine exposure was 1.00 (95% CI, 0.20–4.95), and the risk difference was 0.00 per 100,000 patients (95% CI, –3.47 to 3.47).
Conclusion
Despite studying a very large proportion of US deliveries, we did not find a significant increase in the risk of ACS or AMI in women who received methylergonovine compared with those who did not; estimates were increased only modestly or not at all. The upper limit of the 95% CI of our analysis suggests that treatment with methylergonovine would result in no more than 5 additional cases of ACS and 3 additional cases of AMI per 100,000 exposed patients.
Methylergonovine maleate (Methergine; Novartis Pharmaceuticals Corporation, Plantation, FL) is a semisynthetic ergot alkaloid that acts directly on the smooth muscle of the uterus to cause rapid and sustained contraction. It has a long track record of use to treat postpartum uterine atony, which is the leading cause of postpartum hemorrhage. Because of their effect on smooth muscle, ergot alkaloids (including methylergonovine) can induce vasoconstriction and can cause clinically significant coronary vasospasm. There are several case reports of myocardial ischemia and infarction in association with obstetric exposure to ergot alkaloids, including 1 fatality.
The US Food and Drug Administration (FDA), in the January-March 2012 quarterly report from its Adverse Events Reporting System, identified a “potential signal of serious risk/new safety information” regarding myocardial ischemia and infarction associated with methylergonovine-induced vasospasm. After this, in June 2012, the label for methylergonovine was changed to state that patients with “coronary artery disease or risk factors for coronary artery disease (eg, smoking, obesity, diabetes, high cholesterol) may be more susceptible to developing myocardial ischemia and infarction associated with methylergonovine-induced vasospasm.”
The FDA Adverse Events Reporting System relies on spontaneous reports of adverse events that clinicians attribute to medication exposures. Although, like case reports, the system is useful in generating signals of potential harms that are associated with medications, it lacks both robust capture of events and information about the source population from which those events are drawn. It cannot be used to determine the magnitude of the risks that are associated with a medication, nor can it account for potential confounders of any observed association. Signals of adverse drug effects in the FDA Adverse Events Reporting System must be followed up with pharmacoepidemiologic studies to define properly whether a causal effect is likely to be present and to quantify the magnitude of any observed increase in risk.
To determine the frequency of the postulated risk in routine practice, we sought to measure the occurrence of acute coronary syndrome (ACS) and acute myocardial infarction (AMI) after methylergonovine use in routine care with the use of a very large database of inpatient delivery admissions in the United States. This information can be useful in guiding clinicians’ interpretation of the recent FDA report and label change and their choice of whether to use methylergonovine in the treatment of uterine atony.
Materials and Methods
Cohort
Study data were derived from the Premier Perspective Database, which is a hospital-based health care usage database that has information on approximately one-seventh of all inpatient delivery hospitalizations in the United States for a 4-year period (fourth quarter 2007 to third quarter 2011). The Premier Perspective Database provides these data to hospitals for benchmarking purposes. The database contains information on charges for medications, procedures, blood products, and diagnostic tests during each hospitalization, patient demographic information, and hospital characteristics. Discharge diagnoses are recorded with codes from the International Classification of Diseases, 9th revision , Clinical Modification (ICD-9-CM). This dataset has been used in multiple previous studies to evaluate the safety and effectiveness of various inpatient medications. These data are also used by the FDA for drug safety surveillance and by the Centers for Medicare and Medicaid Services for quality initiatives. The use of this dataset for research was approved by the institutional review board of the Brigham and Women’s Hospital, Boston, MA; a Data Use Agreement was in place.
We identified all inpatient admissions of women who were 12-55 years old for delivery with the use of a validated algorithm as described by Kuklina et al, which accounted for temporal changes in diagnostic coding ( Appendix ; Supplementary Table 1 ). This algorithm identifies delivery admissions by the presence of a diagnosis code for delivery or procedure codes that indicate delivery (eg, cesarean delivery, instrumented vaginal delivery). Hospitalizations with diagnoses that indicate ectopic pregnancy, hydatiform mole, or other abnormal products of conception or procedure codes that indicate abortion were excluded. Although methylergonovine is sometimes used to treat excessive bleeding after miscarriage or abortion, most of these patients are not hospitalized. Therefore, we would not have robust capture of the population that was exposed to methylergonovine in these clinical situations and would be unable to reliably calculate the frequency of the complication of ACS/AMI.
Study exposure and outcomes
Methylergonovine exposure was defined by the presence of a charge code for injectable or oral methylergonovine any time during the delivery hospitalization. The referent group consisted of patients with no such charge.
The primary study outcome was the development of ACS (composite of AMI and unstable angina) defined by ICD-9-CM codes 410.xx (excluding 410.x2) and 411.xx during the delivery hospitalization. As a secondary outcome, we identified the development of AMI that was defined by the presence of ICD-9-CM codes 410.xx (excluding 410.x2). The ICD-9-CM codes for these conditions have been validated and shown to have very high positive predictive values. As the posited mechanism for methylergonovine-induced ACS/AMI is vasospasm, these events, if related to exposure, should occur during the index hospitalization.
Covariates
We identified as covariates conditions that might confound the association between methylergonovine exposure and ACS/AMI: patient demographics, obstetric/medical conditions, markers of the presence, cause and severity of obstetric hemorrhage, and characteristics of the hospital at which the delivery occurred. Demographic factors that were assessed included age (classified into 7 categories), race/ethnicity (classified as white, black, Hispanic, or other/unknown), and calendar year of delivery. Medical/obstetrical conditions were identified by ICD-9-CM codes ( Appendix ; Supplementary Table 2 ) and were chosen for inclusion as covariates based on their previous association with AMI in pregnancy or biologic plausibility as risk factors for ACS/AMI: hypertensive disorders (including preexisting and/or gestational disorder or preeclampsia), diabetes mellitus (preexisting or gestational), chronic ischemic heart disease, chronic renal disease, obesity, dyslipidemia, drug or alcohol abuse, tobacco use, asthma, hypercoagulable conditions, migraine headache, chronic anemia, cesarean delivery, previous cesarean delivery, stillbirth/intrauterine fetal death, multiple gestations, chorioamnionitis, and major puerperal infection.
Because postpartum hemorrhage is an indication for the administration of methylergonovine and has been identified as a risk factor for ACS/AMI, we included multiple variables to identify the presence, cause, and severity of postpartum hemorrhage. The presence and causes of postpartum hemorrhage were identified by ICD-9-CM codes ( Appendix ; Supplementary Table 2 ): hemorrhage from uterine atony, abnormal placentation, uterine rupture, placental abruption, obstetric trauma, hemorrhage caused by coagulopathy, amniotic fluid embolism, and delayed postpartum hemorrhage. Severity was measured by charge codes for the number of units of packed red blood cells that were transfused (categorized as 0, 1-5, 6-9, ≥10), the number of units of fresh frozen plasma that were transfused (categorized as 0, 1-5, 6-9, ≥10), and whether the patient received platelets or cryoprecipitate or had a peripartum hysterectomy.
Characteristics of the hospital where the delivery occurred were also defined, because these may affect the decision to administer uterotonics and/or the accurate diagnosis of ACS/AMI. Hospitals that are accredited by the Association of American Medical Colleges were classified as teaching hospitals. Annual delivery volume was determined for each hospital by the division of the total number of deliveries for each hospital during the study time period by the number of months that the hospital performed ≥1 deliveries and then the multiplication of this figure by 12. Hospitals were then divided into 3 roughly equal-sized groups (in numbers of hospitals) and designated as small, medium, or large delivery centers that corresponded to an annual delivery volume of ≤805, 806-1891, and ≥1892, respectively.
Statistical analysis
To adjust for potential differences between patients who were exposed to methylergonovine and those who were not, we used propensity score matching. A propensity score that predicted methylergonovine exposure was estimated with the use of a logistic regression model that included all the covariates described earlier (patient demographics, obstetric/medical conditions, markers of the presence, cause and severity of obstetric hemorrhage, and characteristics of the hospital at which delivery occurred) without further selection. Patients who had been exposed to methylergonovine were matched to those who had not been exposed to methylergonovine based on propensity score in a 1:1 fixed ratio with a nearest neighbor algorithm with a caliper of 0.05. This resulted in 138,412 matched pairs, such that 99.1% of the methylergonovine-exposed patients were matched to a control subject who had not been exposed. Relative risks and risk differences of ACS and AMI that were associated with methylergonovine exposure were then estimated directly.
Sensitivity and subgroup analyses
As a sensitivity analysis, we estimated the risk of AMI and ACS that were associated with exposure to methylergonovine after adjusting for propensity score decile (as opposed to matching). This approach preserves more of the cohort (in particular the not-exposed) in the analysis and potentially increases the efficiency of the analysis. Patients in the not-exposed group that had a propensity score lower than the lowest value that was observed in the exposed group and patients in the exposed group with a propensity score higher than the highest observed in the not-exposed group were excluded (n = 59); trimming of the tails of the propensity score in this manner may further reduce residual confounding.
We also performed a sensitivity analysis using propensity score matching but excluding deliveries that occurred in hospitals where there were no documented administrations of methylergonovine during the study period (n = 55,836). This was done to ensure that our results were not biased by the potential inclusion of deliveries that occurred in hospitals where methylergonovine administration is not coded reliably.
Finally, we studied the subset of the cohort with known coronary artery disease or coronary disease risk factors, in keeping with the FDA’s drug label revisions. For this analysis, we identified all admissions for patients with ICD-9-CM diagnostic codes that indicated preexisting hypertension, preexisting diabetes mellitus, tobacco use, obesity, chronic renal disease, dyslipidemia, or chronic ischemic heart disease ( Appendix ; Supplementary Table 2 ).
Results
Cohort characteristics
The cohort consisted of 2,233,630 women who were hospitalized for delivery or approximately one-seventh of all deliveries in the United States for the years that were studied. The mean age of the patients in the cohort was 27.7; 51.4% of the women were white. Cesarean delivery occurred in 34.0% of patients. Methylergonovine was administered during the delivery hospitalization to 139,617 patients (6.3%).
There were several important baseline differences between patients who received methylergonovine and those who did not ( Table 1 ). Methylergonovine-exposed patients were somewhat younger than exposed patients who were not exposed, were more likely to be Hispanic, and were less likely to be white or black. They had a higher incidence of all of the causes of obstetric hemorrhage that were assessed and were more likely to be transfused with packed red blood cells, fresh frozen plasma, platelets, and cryoprecipitate. They were more likely to undergo peripartum hysterectomy. They had a lower incidence of hypertensive disorders, obesity, drug abuse, asthma, and previous cesarean delivery and a higher incidence of chronic anemia, cesarean delivery, stillbirth, multiple gestation, chorioamnionitis, and major puerperal infection. They were less likely to deliver at a teaching hospital or a medium-volume delivery center. After propensity score matching, these differences were no longer present, and the absolute difference in the frequency of all measured covariates between the exposed and not-exposed patients was <0.5% ( Table 2 ).
| Variable | Methylergonovine maleate | Difference, % | |
|---|---|---|---|
| Exposed, n (%) | Not exposed, n (%) | ||
| Total | 139,617 | 2,094,013 | |
| Demographics | |||
| Age, y | |||
| 12-19 | 14,538 (10.41) | 195,250 (9.32) | 1.09 |
| 20-24 | 34,561 (24.75) | 489,503 (23.38) | 1.37 |
| 25-29 | 39,650 (28.40) | 595,818 (28.45) | –0.05 |
| 30-34 | 31,706 (22.71) | 506,808 (24.20) | –1.49 |
| 35-39 | 15,395 (11.03) | 248,285 (11.86) | –0.83 |
| 40-44 | 3509 (2.51) | 54,935 (2.62) | –0.11 |
| 44-55 | 258 (0.18) | 3414 (0.16) | 0.02 |
| Race/ethnicity | |||
| White | 68,880 (49.33) | 1,078,758 (51.52) | –2.19 |
| Black | 16,378 (11.73) | 288,592 (13.78) | –2.05 |
| Hispanic | 19,254 (13.79) | 226,627 (10.82) | 2.97 |
| Other/Unknown | 35,105 (25.14) | 500,036 (23.88) | 1.26 |
| Year of delivery | |||
| 2007 | 8858 (6.34) | 130,629 (6.24) | 0.1 |
| 2008 | 35,361 (25.33) | 521,465 (24.90) | 0.43 |
| 2009 | 35,089 (25.13) | 522,008 (24.93) | 0.2 |
| 2010 | 34,039 (24.38) | 516,032 (24.64) | –0.26 |
| 2011 | 26,270 (18.82) | 403,879 (19.29) | –0.47 |
| Cause of obstetric hemorrhage and markers of its severity | |||
| Abnormal placentation | 4717 (3.38) | 22,640 (1.08) | 2.3 |
| Postpartum hemorrhage caused by uterine atony | 19,410 (13.90) | 22,915 (1.09) | 12.81 |
| Amniotic fluid embolism | 31 (0.02) | 74 (0.00) | 0.02 |
| Postpartum hemorrhage caused by coagulopathy | 795 (0.57) | 3648 (0.17) | 0.4 |
| Delayed postpartum hemorrhage | 2050 (1.47) | 3128 (0.15) | 1.32 |
| Uterine rupture | 144 (0.10) | 984 (0.05) | 0.05 |
| Placental abruption | 2016 (1.44) | 21,504 (1.03) | 0.41 |
| Antepartum hemorrhage from other sources | 653 (0.47) | 6030 (0.29) | 0.18 |
| Obstetric trauma | 10,808 (7.74) | 140,088 (6.69) | 1.05 |
| Packed red blood cells (units) | |||
| 0 | 133,312 (95.48) | 2,078,170 (99.24) | –3.76 |
| 1-5 | 5580 (4.00) | 14,893 (0.71) | 3.29 |
| 6-9 | 469 (0.34) | 670 (0.03) | 0.31 |
| ≥10 | 256 (0.18) | 280 (0.01) | 0.17 |
| Fresh frozen plasma (units) | |||
| 0 | 138,386 (99.12) | 2,092,159 (99.91) | –0.79 |
| 1-5 | 967 (0.69) | 1520 (0.07) | 0.62 |
| 6-9 | 157 (0.11) | 214 (0.01) | 0.1 |
| ≥10 | 107 (0.08) | 120 (0.01) | 0.07 |
| Cryoprecipitate | 422 (0.30) | 507 (0.02) | 0.28 |
| Platelets | 157 (0.11) | 405 (0.02) | 0.09 |
| Peripartum hysterectomy | 636 (0.46) | 1398 (0.07) | 0.39 |
| Medical and obstetric conditions | |||
| Preexisting hypertension | 1491 (1.07) | 45,246 (2.16) | –1.09 |
| Gestational hypertension | 3294 (2.36) | 75,697 (3.61) | –1.25 |
| Preexisting hypertension with superimposed preeclampsia | 278 (0.20) | 11,946 (0.57) | –0.37 |
| Mild preeclampsia | 1863 (1.33) | 50,322 (2.40) | –1.07 |
| Severe preeclampsia/eclampsia | 876 (0.63) | 31,033 (1.48) | –0.85 |
| Preexisting diabetes mellitus | 1041 (0.75) | 19,022 (0.91) | –0.16 |
| Gestational diabetes mellitus | 7902 (5.66) | 116,709 (5.57) | 0.09 |
| Chronic ischemic heart disease | 16 (0.01) | 312 (0.01) | 0 |
| Chronic renal disease | 368 (0.26) | 5313 (0.25) | 0.01 |
| Obesity | 4980 (3.57) | 80,503 (3.84) | –0.27 |
| Dyslipidemia | 82 (0.06) | 1519 (0.07) | –0.01 |
| Drug abuse | 1574 (1.13) | 27,339 (1.31) | –0.18 |
| Alcohol abuse | 158 (0.11) | 2161 (0.10) | 0.01 |
| Tobacco use | 7954 (5.70) | 135,032 (6.45) | –0.75 |
| Asthma | 4333 (3.10) | 69,247 (3.31) | –0.21 |
| Hypercoagulable state | 409 (0.29) | 6378 (0.30) | –0.01 |
| Migraine headache | 684 (0.49) | 9992 (0.48) | 0.01 |
| Chronic anemia | 17,096 (12.24) | 168,700 (8.06) | 4.18 |
| Cesarean delivery | 49,033 (35.12) | 710,555 (33.93) | 1.19 |
| Previous cesarean delivery | 18,131 (12.99) | 345,487 (16.50) | –3.51 |
| Stillbirth | 1042 (0.75) | 12,480 (0.60) | 0.15 |
| Multiple gestation | 4422 (3.17) | 38,218 (1.83) | 1.34 |
| Chorioamnionitis | 4273 (3.06) | 31,224 (1.49) | 1.57 |
| Major puerperal infection | 856 (0.61) | 6249 (0.30) | 0.31 |
| Hospital characteristics | |||
| Teaching hospital | 43,929 (31.46) | 763,859 (36.48) | –5.02 |
| Delivery volume | |||
| Low | 13,365 (9.57) | 173,308 (8.28) | 1.29 |
| Medium | 32,545 (23.31) | 535,842 (25.59) | –2.28 |
| High | 93,707 (67.12) | 1,384,863 (66.13) | 0.99 |
| Variable | Methylergonovine maleate | Difference, % | |
|---|---|---|---|
| Exposed, n (%) | Not exposed, n (%) | ||
| Total | 138,412 | 138,412 | |
| Demographics | |||
| Age, y | |||
| 12-19 | 14,419 (10.42) | 14,636 (10.57) | –0.15 |
| 20-24 | 34,263 (24.75) | 34,468 (24.90) | –0.15 |
| 25-29 | 39,305 (28.40) | 39,155 (28.29) | 0.11 |
| 30-34 | 31,425 (22.70) | 31,272 (22.59) | 0.11 |
| 35-39 | 15,262 (11.03) | 15,128 (10.93) | 0.1 |
| 40-44 | 3484 (2.52) | 3510 (2.54) | –0.02 |
| 44-55 | 254 (0.18) | 243 (0.18) | 0 |
| Race/ethnicity | |||
| White | 68,314 (49.36) | 68,350 (49.38) | –0.02 |
| Black | 16,276 (11.76) | 16,121 (11.65) | 0.11 |
| Hispanic | 19,010 (13.73) | 19,196 (13.87) | –0.14 |
| Other/unknown | 34,812 (25.15) | 34,745 (25.10) | 0.05 |
| Year of delivery | |||
| 2007 | 8781 (6.34) | 8613 (6.22) | 0.12 |
| 2008 | 35,008 (25.29) | 35,053 (25.33) | –0.04 |
| 2009 | 34,769 (25.12) | 34,682 (25.06) | 0.06 |
| 2010 | 33,770 (24.40) | 33,990 (24.56) | –0.16 |
| 2011 | 26,084 (18.85) | 26,074 (18.84) | 0.01 |
| Cause of obstetric hemorrhage and markers of its severity | |||
| Abnormal placentation | 4580 (3.31) | 4638 (3.35) | –0.04 |
| Postpartum hemorrhage caused by uterine atony | 18,518 (13.38) | 18,617 (13.45) | –0.07 |
| Amniotic fluid embolism | 28 (0.02) | 15 (0.01) | 0.01 |
| Postpartum hemorrhage caused by coagulopathy | 703 (0.51) | 582 (0.42) | 0.09 |
| Delayed postpartum hemorrhage | 1958 (1.41) | 1965 (1.42) | –0.01 |
| Uterine rupture | 137 (0.10) | 123 (0.09) | 0.01 |
| Placental abruption | 1986 (1.43) | 2026 (1.46) | –0.03 |
| Antepartum hemorrhage from other sources | 643 (0.46) | 634 (0.46) | 0 |
| Obstetric trauma | 10,667 (7.71) | 10,755 (7.77) | –0.06 |
| Packed red blood cells (units) | |||
| 0 | 132,654 (95.84) | 133,098 (96.16) | –0.32 |
| 1-5 | 5137 (3.71) | 4866 (3.52) | 0.19 |
| 6-9 | 402 (0.29) | 305 (0.22) | 0.07 |
| ≥10 | 219 (0.16) | 143 (0.10) | 0.06 |
| Fresh frozen plasma (units) | |||
| 0 | 137,344 (99.23) | 137,605 (99.42) | –0.19 |
| 1-5 | 844 (0.61) | 662 (0.48) | 0.13 |
| 6-9 | 138 (0.10) | 86 (0.06) | 0.04 |
| ≥10 | 86 (0.06) | 59 (0.04) | 0.02 |
| Cryoprecipitate | 344 (0.25) | 238 (0.17) | 0.08 |
| Platelets | 129 (0.09) | 90 (0.07) | 0.02 |
| Peripartum hysterectomy | 566 (0.41) | 469 (0.34) | 0.07 |
| Medical and obstetric conditions | |||
| Preexisting hypertension | 1486 (1.07) | 1627 (1.18) | –0.11 |
| Gestational hypertension | 3281 (2.37) | 3592 (2.60) | –0.23 |
| Preexisting hypertension with superimposed preeclampsia | 278 (0.20) | 334 (0.24) | –0.04 |
| Mild preeclampsia | 1856 (1.34) | 2098 (1.52) | –0.18 |
| Severe preeclampsia/eclampsia | 872 (0.63) | 1038 (0.75) | –0.12 |
| Preexisting diabetes mellitus | 1036 (0.75) | 988 (0.71) | 0.04 |
| Gestational diabetes mellitus | 7822 (5.65) | 7836 (5.66) | –0.01 |
| Chronic ischemic heart disease | 16 (0.01) | 7 (0.01) | 0 |
| Chronic renal disease | 357 (0.26) | 351 (0.25) | 0.01 |
| Obesity | 4,933 (3.56) | 5049 (3.65) | –0.09 |
| Dyslipidemia | 80 (0.06) | 67 (0.05) | 0.01 |
| Drug abuse | 1,569 (1.13) | 1510 (1.09) | 0.04 |
| Alcohol abuse | 157 (0.11) | 131 (0.09) | 0.02 |
| Tobacco use | 7,911 (5.72) | 7699 (5.56) | 0.16 |
| Asthma | 4,310 (3.11) | 4131 (2.98) | 0.13 |
| Hypercoagulable state | 408 (0.29) | 372 (0.27) | 0.02 |
| Migraine headache | 679 (0.49) | 623 (0.45) | 0.04 |
| Chronic anemia | 16,786 (12.13) | 17,163 (12.40) | –0.27 |
| Cesarean delivery | 48,574 (35.09) | 49,092 (35.47) | –0.38 |
| Previous cesarean delivery | 18,026 (13.02) | 17,565 (12.69) | 0.33 |
| Stillbirth | 1029 (0.74) | 1012 (0.73) | 0.01 |
| Multiple gestation | 4330 (3.13) | 4556 (3.29) | –0.16 |
| Chorioamnionitis | 4150 (3.00) | 4339 (3.13) | –0.13 |
| Major puerperal infection | 823 (0.59) | 809 (0.58) | 0.01 |
| Hospital characteristics | |||
| Teaching hospital | 43,666 (31.55) | 43,608 (31.51) | 0.04 |
| Delivery volume | |||
| Low | 13,250 (9.57) | 13,464 (9.73) | –0.16 |
| Medium | 32,346 (23.37) | 32,130 (23.21) | 0.16 |
| High | 92,816 (67.06) | 92,818 (67.06) | 0 |
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