Ergometrine for postpartum hemorrhage and associated myocardial ischemia: Two case reports and a review of the literature

Abstract Ergometrine is recommended for use in the medical treatment of postpartum hemorrhage. Ergometrine can occasionally precipitate myocardial ischemia in the setting of significant anemia in women without preexisting cardiac risk factors, and it is important to recognize and treat myocardial ischemia in affected patients to prevent severe complications.


| BACKGROUND
Ergot analogues are commonly administered to women for treatment of postpartum hemorrhage secondary to uterine atony. We describe two cases of women who developed myocardial ischemia due to coronary artery vasospasm following administration of the ergot analogue ergometrine for control of postpartum bleeding and present a literature review of similar cases for comparison. Myocardial ischemia is a rare acute complication of the administration of ergometrine and its analogues in obstetric and gynecologic patients in the absence of preexisting cardiac risk factors. It is important to recognize the rare possibility of inducing myocardial ischemia with ergometrine administration in patients without significant preexisting cardiac risk factors, particularly in the setting of anemia secondary to postpartum hemorrhage.
The ergot analogue ergometrine is recommended by the Royal College of Obstetricians and Gynaecologists as a second-line pharmaceutical agent for the treatment of uterine atony in cases of postpartum hemorrhage after first-line oxytocin administration. 1 In the context of the anemia and hypovolemia that may result from acute postpartum hemorrhage, the administration of ergometrine may rarely precipitate coronary vasospasm and the potential for myocardial ischemia should be recognized as a rare but serious complication 2-14 with a mortality rate as high as 18%. 15 It is important to recognize the potential for myocardial ischemia in patients with no prior risk factors and to correct reversible causes promptly to reduce or prevent morbidity and mortality from myocardial ischemia and infarction. We describe two cases of myocardial ischemia in the context of postpartum hemorrhage and ergometrine administration.

| Case one
Patient one was a 48-year-old woman at 35-week gestation (gravida 3 para 2 following in vitro fertilization) who underwent emergency cesarean section for a fourth antepartum hemorrhage of 300 mL after three prior antepartum hemorrhages of unknown etiology between 27 and 35 weeks, without evidence of placenta previa. On examination prior to her surgery, she was hemodynamically stable (heart rate [HR] 76 beats per minute [bpm], blood pressure [BP] 110/70 mm Hg) with a hemoglobin (Hb) of 98 g/L, ferritin of 73 μg/L, and Kleihauer negative. She had been diagnosed with gestational diabetes at 26-week gestation, successfully controlled with dietary modification alone. She was a nonsmoker with no family history of heart disease and no personal history of dyslipidemia, hypertension, diabetes preceding pregnancy, chronic renal disease, or obesity. She had previously been diagnosed with panic disorder and bulimia nervosa. Her prepregnancy body mass index (BMI) was 22.1 kg/m 2 .
Under spinal anesthetic, a lower-segment cesarean section was performed, with delivery of a live male infant weighing 2480 g. One hundred micrograms (mcg) of carbetocin was administered at time of delivery. The placenta was delivered piecemeal, and the uterus was exteriorized to place 2 hemostatic sutures to venous sinuses at the placental bed. A total of 500-mcg ergometrine was administered intraoperatively as per institutional policy for uterine atony in two 125-mcg intravenous (IV) doses and one 250-mcg intramuscular (IM) dose. Six mL of prostaglandin F2 alpha was injected into the uterine fundus for ongoing bleeding, and after closure of one uterine layer, a B-Lynch suture was placed with 0 polydioxanone suture (PDS) to further control uterine bleeding. The second uterine layer was then closed, at which time the patient became anxious and agitated and a decision was made to administer a general anesthetic and intubate the patient. Hemostasis was achieved with closure of the second uterine layer, estimated blood loss for the procedure was 2000 mL, and the patient remained hemodynamically stable throughout the procedure. The postoperative hemoglobin was 67 g/L without ongoing bleeding, and the patient was transfused one unit of packed red blood cells in accordance with institutional policy.
The following morning, 8 hours postoperatively, the patient complained of shortness of breath and a sensation of blockage in her neck and chest without radiation to her back, jaw, or arm. On examination, the HR was 86 bpm, BP was 105/66 mm Hg, and a soft systolic ejection murmur was audible. There were no signs of cardiac failure. Electrocardiogram (ECG) showed sinus rhythm with normal axes and no ischemic changes. Her hemoglobin, 8 hours postoperatively, was 79 g/L. Troponin T was 83 ng/L (normal range < 14 ng/L) on initial review, and 4 hours later, her ECG was unchanged and the patient's troponin T fell to 55 ng/L (Δ−28 ng/L [−33%]). Transthoracic echocardiogram demonstrated normal left ventricular size and function, a mildly dilated left atrium, mild mitral regurgitation with thickened, mobile leaflets, and mild-to-moderate tricuspid regurgitation. Type 2 acute myocardial infarction (AMI) was diagnosed, thought to be secondary to anemia and ergometrine administration, with functional mitral regurgitation. A treatment target hemoglobin of 100 g/L was adopted, and the patient was transfused three units of packed red blood cells with a final hemoglobin of 101 g/L being reached 3 days postoperatively. The patient received prophylactic anticoagulation with enoxaparin postoperatively, but did not require any other therapy for treatment of AMI. The symptoms settled spontaneously 24 hours postoperatively, and the patient remained asymptomatic thereafter.
The patient was discharged home on day 15 postdelivery, with the discharge delay being due to her complex psychosocial situation. Three weeks postdelivery, the patient underwent computed tomography (CT) coronary angiography which found no evidence of coronary atherosclerosis and noncontrast CT scanning found her CT coronary artery score to be zero, corresponding to a <1% chance of myocardial infarction over 10 years. 16

| Case two
Patient two was a 35-year-old woman, gravida 2 para 1 with a background of a small persistent perimembranous congenital ventricular septal defect (VSD) for which she was asymptomatic. Echocardiogram in her first pregnancy determined that the VSD was of limited clinical significance. She had diet-controlled gestational diabetes and an otherwise unremarkable antenatal course. Her father had suffered a fatal myocardial infarction at the age of 62, but the patient was a nonsmoker with no history of dyslipidemia, hypertension, preexisting diabetes, chronic renal disease, or obesity.
She presented in spontaneous labor at 39 + 2 weeks gestation. Following a 2-hour and 1-minute first stage of labor and a 16-minute second stage of labor without analgesia, a live male infant weighing 3140 g was delivered vaginally. The patient was administered 10 units of Syntocinon IM with delivery. Despite an estimated postpartum blood loss of 1000 mL, the patient was hemodynamically stable with HR 66 bpm and BP 105/65 mm Hg. The patient was administered an IV infusion of 40 units Syntocinon over 4 hours 250 mcg of ergometrine IV for postpartum hemorrhage. The uterus remained atonic but responded to bimanual palpation and clot evacuation from the vagina and cervix. A further 250 mcg of ergometrine was administered IM. Examination at that time revealed a grade 3C perineal tear, and the patient was taken to theater for perineal repair under spinal anesthesia.
During repair, the patient lost a further 1800 mL of blood secondary to uterine atony and perineal trauma, and the patient was noted to have ST elevation of 2-3 mm on cardiac monitoring approximately 1 hour after ergometrine administration. This was associated with a complaint of chest tightness, dizziness, and nausea although the HR (80 bpm) and BP (100/40 mm Hg) remained unchanged. One liter of IV crystalloid fluids and noninvasive oxygen supplementation was | 2435 SPENCER aNd LOWE administered, and cardiac monitoring demonstrated sinus rhythm with normalization of the ST segment. The patient was transfused 3 units of packed red blood cells and administered 1-g tranexamic acid. Postoperatively, a 12-lead ECG demonstrated sinus rhythm with ST depression of 1 mm in the inferolateral leads (V4-6, II, aVF). Investigations at the time demonstrated that the hemoglobin had fallen from 137 g/L on admission to 74 g/L day 1 postoperatively, and serial troponin T testing showed an increase from 7 to 197 ng/L over 6 hours. Chest X-ray was within normal limits. The patient received enoxaparin 40 mg daily for postoperative thromboembolic prophylaxis but did not require therapeutic anticoagulation or invasive cardiac intervention. The patient was transfused one further unit of packed red blood cells, and on day 2 postoperatively, the Hb had returned to 103 g/L with a troponin T level of 88 ng/L. Transthoracic echocardiogram on day 3 after delivery demonstrated normal systolic function with no regional wall abnormalities and normal valvular function. The VSD was noted to be present. The patient was discharged home on day 4 of admission. Six weeks postdelivery, the patient underwent stress echocardiography which demonstrated no inducible coronary ischemia.

| DISCUSSION
Ergometrine (ergonovine) is a crystalline alkaloid extract of ergot that is commonly used in obstetric cases to induce tonic uterine contraction through its action on uterine smooth muscle. The amplitude and frequency of uterine contractions and uterine tone are increased; lesser doses see this increased uterine activity interspersed with periods of relaxation, increased doses demonstrate sustained uterine tone without relaxation with a subsequent reduction in uterine blood flow, and the contraction of the uterine wall around bleeding vessels at the placental bed contributes to hemostasis. 17 Ergometrine also has a vasoconstrictive effect, which can be seen in the disease ergotism whereby damp cereal crops contaminated with ergot-containing fungus cause progressive vasospasm leading to peripheral ischemia and eventual gangrene. 18 This vasoconstrictive effect can be used in the provocation of coronary artery vasospasm in cardiac catheterization procedures but has lost favor to acetylcholine, which has a shorter duration of action with less risk of infarction. 9 Ergometrine is recommended by the Royal College of Obstetricians and Gynaecologists (RCOG) in secondline pharmacological management of postpartum hemorrhage due to uterine atony 1 after first-line administration of oxytocin (Syntocinon). This management approach is supported in the American College of Obstetricians and Gynecologists (ACOG) practice bulletin for postpartum hemorrhage where methylergonovine is recommended as second-line pharmacological agent 19 after oxytocin. The Royal Australian and New Zealand College of Obstetricians and Gynaecologists (RANZCOG) also recommends ergometrine as a second-line pharmacological agent (after oxytocin) in the management of postpartum hemorrhage due to insufficient uterine tone, 20 but note is made in the guideline of the difficulty in conducting randomized controlled trials for uterotonics in postpartum hemorrhage, and thus, ergometrine has not been well studied in this context.
Ergometrine may be administered IV or IM. The IV route has an immediate onset of uterine contraction but may need to be readministered every 2-4 hours as necessary, and the patient should be monitored for hypertension, while IM administration has onset of uterine contractions within 2-5 minutes and is less likely to precipitate hypertension. 21 Use of Syntometrine (ergometrine-oxytocin) vs oxytocin alone has been shown to provide a very mild benefit in prophylaxis against primary postpartum hemorrhage >500 mL, but this benefit is not observed with blood loss >1000 mL. 22 Studies suggest that the incidence of myocardial infarction during pregnancy is between 1 in 16 129 deliveries 23 and 1 in 35 700 deliveries 24 ; however, the mortality rate has been estimated to be as high as 18%. 15 This high mortality is concerning for a condition that may be rare and difficult to recognize in a patient population that is not traditionally associated with ischemic heart events. Recognizing factors that may predispose myocardial ischemia-such as ergot (including ergometrine and methylergometrine) administration in the setting of hemorrhage, anemia, and the intravascular volume depletion that severe postpartum hemorrhage may precipitate-is crucially important. Anemia may not be recognized as visual estimation of blood loss is liable to underestimate blood loss, and signs of hypovolemic shock are less sensitive in pregnancy. 1 We conducted a search of the literature in PubMed and MEDLINE using the terms ["ergometrine" or "ergonovine" or "methylergonovine"] and "myocardial ischemia" or "myocardial infarction" or "acute coronary syndrome" and additionally searched references of review articles for cases of ergot-related myocardial events. This search was performed in November 2016 and repeated in February 2018. Myocardial ischemia in the context of postpartum hemorrhage managed with ergots has been described previously but is very rare. 2,4,[6][7][8][9]14,25,26 In three of the nine cases, the women had no preexisting cardiac risk factors. 6,8,25 Myocardial ischemia has also been described in three cases when patients were administered oral ergots for induction of abortion, 27,28 in three patients for routine prophylaxis against hemorrhage following dilatation and curettage 5,13,29 and in one patient for treatment of abnormal uterine bleeding. 3 These cases demonstrate that ergot administration is not without the risk of severe side effects even in young women without any objective cardiac risk factors. During resuscitation of a patient with postpartum