Ovarian Hyperstimulation Syndrome and Myocardial Infarction: A Systematic Review

Background: Ovarian hyperstimulation syndrome (OHSS) is a rare but serious complication of ovarian stimulation occurring during assisted reproduction technologies (ART). It is characterized by increased vascular permeability and hypercoagulable states resulting in strokes and peripheral ischemia. Acute myocardial infarction and cardiac thrombosis, however, have been rarely reported complications of OHSS. Methods: A literature search was performed for reports on myocardial infarction and cardiac thrombosis associated with ovarian stimulation with a summary of their clinical characteristics. Results: A total of twelve published cases were reviewed with 5 out of 12 (41.67%) of the reported cases were 35 years of age or older. Myocardial infarction was reported in 10 out of the 12 cases (83.3%). Two of the cases were pregnant at presentation (16.67%). The mean duration between starting ovarian stimulation medications and clinical presentation was 23 days. Chest pain was the most common presenting symptom (66.67%), 2 cases presented with stroke (16.67%) and 2 cases presented with abdominal distention (16.67%). A total of 8 patients underwent coronary angiography with 2 of these cases were treated with percutaneous coronary intervention. No mortality reported in any of the twelve cases. Conclusion: Women of a relatively younger age undergoing ovarian stimulation may be at risk for developing myocardial infarction and cardiac thrombosis. Once thrombosis is suspected, initiating appropriate therapy in a timely manner is crucial.


Introduction
The use of ovarian stimulation has increased exponentially over the past few decades, as there have been significant advancements in reproductive technology. However, with increased use of ovarian stimulation, there have been reports of increasing numbers of ovarian hyperstimulation syndrome (OHSS) and hypercoagulable states despite protocols in place to minimize these complications [1]. Ovarian hyperstimulation syndrome is a complication which affects women taking hormonal medications to stimulate oocyte development in the ovaries, which can cause serious psychological and physiological derangements and, in rare cases, may leads to maternal death [2]. Ovarian hyperstimulation syndrome is classified according to disease severity as mild, moderate or severe. It is characterized by ovarian enlargement, fluid shifts into the third space, hypovolemia, hemoconcentration, serosal effusions, ascites and renal failure; and in some cases, hypercoagulation [3]. Multiple case reports of ovarian stimulation-associated cardiac thrombosis have been published. The aim of this systematic review of the case reports is to describe the clinical characteristics of cardiac thrombosis in these cases. We also aim to provide a brief literature review on the subject.

Methods
On October 2018, a systematic search was conducted using PubMed and Google Scholar to review case reports about myocardial infarction or cardiac thrombosis precipitated by ovarian stimulation. Studies that listed the keywords "Myocardial infarction, cardiac thrombosis, ovarian stimulation, ovarian hyperstimulation syndrome" were used to identify case reports. The reference list of each report was checked for additional cases. Data reviewed included demographic data, cardiovascular risk factors, medication(s) used for ovarian stimulation, parity, thrombophilia, electrocardiography (EKG), cardiac enzymes, echocardiography, time of presentation, complications, management, and outcome.
Two of the cases were pregnant at presentation (16.67%). Prevalence of cardiovascular risk factors and co-morbidities in the reported cases were as follows: hypertension, diabetes and obesity in 1 case (8.33%), active smoking in 3 cases (25%), antiphospholipid syndrome in 2 cases (16.67%), polycystic ovarian disease in 3 cases (25%), 1 case with bicuspid aortic valve (8.33%), and 1 case of premature ovarian failure (8.33%). Most of the reported cases presented with chest pain (66.67%), 2 cases presented with stroke (16.67%) and 2 cases presented with abdominal distention (16.67%). The mean time between starting ovarian stimulation medications and presentation was 23 days. Elevated troponin levels were reported in 8 cases (66.67%). Management of myocardial infarction associated with ovarian stimulation included anticoagulation (low molecular weight heparin and heparin), antiplatelet therapy (aspirin and clopidogrel). Supportive therapy was provided to all acses in the form of correction of hypoalbuminemia and intravenous fluid replacement. A total of 8 patients underwent coronary angiography, with two of them treated with percutaneous coronary intervention. Therapeutic abortion was not utilized in the two reported pregnant patients. One case was treated with surgical intervention due to an associated sinus of valsalva aneurysm. One case was complicated with a cerebrovascular accident. No mortalities were reported in any of the cases.

Discussion
Coronary heart disease is still, despite medical advancements, the leading cause of death in adults. The American Heart Association (AHA) has reported that 15.5 million person's ≥20 years of age in the USA have coronary heart disease [16]. It causes about one-third of all deaths in the population older than 35 years [17]. Myocardial infarction in young females are commonly due to coronary artery thrombosis from hypercoagulable states such as antiphospholipid syndrome, protein S and factor XII deficiencies; embolization, spasm, dissection, accelerated thrombosis, or coronary anomalies [18,19].
In this review, we reported 9 cases of myocardial infarctions and 3 cases of cardiac thrombosis, related to ovarian stimulation. The pathophysiology of ovarian hyperstimulation syndrome is not completely understood. It is likely that when the ovaries are exposed to exogenous stimulating hormones there is a cascade of proinflammatory mediator production such as vascular endothelial growth factor (VEGF), interleukins, tumor necrosis factor-α, and endothelin-1; which mediates increases in vascular permeability and capillary leakage into the third space [20]. These changes will lead to hemoconcentration, hypovolemia, hypercoagulable states and renal dysfunction. On the other hand, ascites and ovarian enlargement contribute to decreased venous return which in turn precipitates thrombus formation [21]. Co-morbidity of hypercoagulable states such as antiphospholipid syndrome can increase the risk of thrombosis as in the two cases in our review [7,10]. The majority of the cases in the review, however, had no history of hypercoagulable states, which indicate that OHSS can be considered as a risk factor for hypercoagulability leading to thrombosis and myocardial infarction.
Management of myocardial thrombosis associated with OHSS is hydration, anticoagulation and antiplatelet therapy. Percutaneous coronary intervention should be considered in all cases of myocardial infarction given the reports of favorable outcomes. Literature support the success of PCI with or without coronary artery stenting in hypercoagulable states as in antiphospholipid syndrome [22]. In the cases of OHSS with MI during pregnancy, PCI is still recommended as Coronary angiography exposes patients to 2.5-5.0 mSv (equivalent to 125-250 chest x-rays), and PCI exposes patients to 5.0-15.0 mSv (equivalent to 115-1000 chest x-rays); both are below the threshold for teratogenicity at any gestational age [23]. The use of thrombolytic therapy in pregnancy is still debatable as there is no scientific data on its safety [24].

Conclusion
Myocardial infarction and cardiac thrombosis are very serious complications of OHSS. Women undergoing ovarian stimulation may be at risk for developing thrombosis secondary to OHSS. Detailed assessment before ovarian stimulation is essential to detect history of preexisting hypercoaguable conditions or previous history of thrombosis that may necessitate the consideration of alternative infertility interventions in these high-risk patients. Furthermore, once OHSS is diagnosed prompt therapy should be instituted including supportive therapy such as fluid replacement and close monitoring to minimize the risk of these potentially fatal complications.