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Ovarian Hyperstimulation Syndrome

Case Introduction

A 30 year old G1P1 female presents to the Emergency Department with a chief complaint of abdominal pain. She states that 72 hours prior she had an egg retrieval out of state and she had two injections of an “unknown hormone”. She states the procedure went well and she was fine until today. She also endorses bloating, swelling and shortness of breath.
On exam, her HR is 130-140 and her BP is soft around 99/76. She is healthy appearing and non toxic. Her abdomen is distended, ascitic and non focally tender. She is not peritonitic. Formal US identified enlarged ovaries approximately 10 x 10 x 10 cm with numerous heterogeneous mixed solid and cystic lesions consistent with ovarian hyperstimulation syndrome. Complete blood count reveals a leukocytosis of 20.62, hemoglobin of 13.1 and platelets of 347. Her metabolic panel was reassuring, she was not pregnant.

Ovarian Hyperstimulation Syndrome

Ovarian Hyperstimulation Syndrome (OHSS) is an “iatrogenic complication of assisted reproduction technology”.1Kumar, Pratap, et al. “Ovarian hyperstimulation syndrome.” Journal of human reproductive sciences 4.2 (2011): 70-75. Clinically, it is characterized by cystic enlargement of the ovaries and a fluid shift from intravascular into the third space. This occurs due to increased capillary permeability and ovarian neogenesis. It occurs secondary to the administration of human chorionic gonadotropin (hCG) and is extremely rare without it. It’s impact can be very serious and fatal cases have been reported.
Transabdominal view of OHSS. Note the enlarged, multi-cystic ovaries.
OHSS is thought to be mediated via the production of angiogenic molecule VEGF via stimulation by hCG. The incidence ranges between 3% and 6% and the more severe form between 0.1% and 3%. It has two clinical presentations. The first presentation is the early form, characterized as occurring within days after the ovulating trigger of hCG administration and an exaggerated response to the gonadotropin stimulation. The late form presents more than 10 days after hCG and is mainly related to the secretion of placental hCG.2Abramov Y, Elchalal U, Schenker JG. Severe OHSS: An ‘epidemic’ of severe OHSS: A price we have to pay? Hum Reprod. 1999;14:2181–3 The late cases constitute an early form of pregnancy and are serious and long lasting.
The pathophysiology is not entirely understood. It is thought to occur secondary to increased vascular permeability surrounding the ovaries and their vasculature. 3Morris RS, Paulson RJ. Ovarian derived prorenin-angiotensin cascade in human reproduction. FertilSteril. 1994;62:1105–14 In addition to hCG, estrogen, estradiol, prolactin, histamine and prostaglandins have all been implicated. However, it is now thought that the primary pathophysiology occurs due to secretion of vasoactive substances including interleukins, tumor necrosis factor (TNF)-α, endothelin-1 and VEGF. Subsequently, increased vascular permeability around the ovaries occurs.
ovarian hyperstimulation syndrome pathophysiology
Description of the pathophysiology of OHSS.1Chen, Chin-Der, et al. "Update on management of ovarian hyperstimulation syndrome." Taiwanese Journal of Obstetrics and Gynecology 50.1 (2011): 2-10.
Primary risk factors include young age, history of exaggerated response to gonadotrophins, previous OHSS and a history of polycystic ovarian syndrome (PCOS).4Lee TH, Liu CH, Huang CC, Wu YL, Shih YT, Ho HN, et al. Serum anti-mullerian hormone and estradiol levels as predictors of ovarian hyperstimulation syndrome in assisted reproduction technology cycles. Hum Reprod. 2008;23:160–7 Several studies have looked at laboratory values which can predict the development of OHSS however none have been shown to be reliable.
Clinical features include abdominal pain, nausea and vomiting. Enlargement of the ovaries can be as great as 25 cm. Patients develop ascites and may have localized or generalized peritonitis secondary to ruptured cysts, protein rich fluid and inflammatory markers. Acute abdominal pain can occur due to ovarian torsion, hemorrhage or cystic rupture.
classification of severity of ovarian hyperstimulation syndrome
Classification of severity of ovarian hyperstimulation syndrome2Sobhy, Amr, et al. "Evaluation of the value of hypertonic saline as adjuvant treatment of severe ovarian hyperstimulation syndrome." Ain Shams Journal of Anesthesiology 10.1 (2017).
Patient’s are often hypotensive and/or hypovolemic. There is a massive fluid shift and third spacing resulting in the development of edema, ascites, hydrothorax and/or hydropericardium.5Insler V, Lunenfeld B. Pathogenesis of ovarian hyperstimulation syndrome. In: Gomel V, Leung PC, editors. in vitro fertilization and assisted reproduction. Bologna Italy: MonduzziEditore; 1997. pp. 433–9. Patient’s may be dyspneic due to pleural effusion, pulmonary edema and more severe manifestations such as pulmonary embolism and acute respiratory distress syndrome. Patients have an increased risk of venous thromboembolism. Due to fluid shifts, electrolyte imbalances have been reported. Patients tend to develop hyperkalemia and acidosis.6Polishuk WZ, Schenker JG. Ovarian overstimulation syndrome. Fertil Steril. 1969;20:443–50. Finally, acute renal failure can occur.
OHSS can be classified into mild, moderate and severe cases. Mild cases are limited to abdominal distension, discomfort and require primarily supportive control. Moderate cases include mild presentation plus ultrasonographic evidence of ascites. Finally, severe cases inclead features of OHSS plus ascites, pleural effusion and/or dyspnea. Severe cases may also have hemoconcentration, coagulopathies, acute renal injury.
Obstetricians have attempted to institute protocols to prevent development of OHSS. Conceptually, the aim is to stimulate the ovaries without exceeding the FSH threshold and subsequent exaggerated response. This can be performed by “cycle cancellation”, “coasting” and “modification of the triggering agent”. The description of these is beyond the scope of this case report.
Additional prevention strategies have also been used. Prophylactic administration of albumin or hydroxyethyl starch solution are used to increase the plasma oncotic pressure. Because GnRH agonists are associated with OHSS, antagonist protocols have been shown to lower the incidence of severe OHSS.7Al-Inany HG, Abou-Setta AM, Aboulghar M. Gonadotrophin- releasing hormone antagonists for assisted conception. Cochrane Database Syst Rev. 2006;3:CD001750. Avoidance of hCG for luteal phase support has been suggested and in vitro maturation of oocytes offers potential to reduce the incidence of OHSS. Insulin sensitizing agents such as metformin, dopamine agonism and aspirin have all been used to help reduce the risk of OHSS.
Treatment is driven by the degree of OHSS. Mild cases are essentially supportive. Women with mild disease should be monitored for progression to moderate or severe disease. Moderate cases require observation, bed rest, monitoring of labs and intake/output. Positive fluid balances should clue the clinician into disease progression rather than resolution. Resolution of OHSS is characterized by shrinking cysts as seen on two consecutive ultrasound exams and when clinical symptoms recede. Progression to severe OHSS is marked by continuous weight gain, increasing severity of symptoms or new symptoms.
Severe OHSS requires admission to the hospital and sometimes to the Intensive Care Unit. These patients are routinely admitted to the hospital with fluid balances assessed multiple times per day. Managing and maintaining intravascular volume is the primary treatment. Simultaneously, physicians need to correct electrolyte imbalances and complications of ascites and pleural effusion and prevention of venous thromboembolism. Commonly used fluids include dextrose 5% normal saline (D5NS) with close monitoring. Human albumin should be given if urine output is not satisfactory. For ascites, paracentesis is performed. Worsening features require admission to the intensive care unit.

Case Outcome

Formal ultrasound confirmed diagnosis of OHSS. Ultimately, it was determined that clomiphene was administered. The patient was admitted to the OBGYN service and placed on leuprolide (GnRH agonist), letrozole (aromatase inhibitor). She had low UOP (5-25 ml/hr) despite aggressive IV fluids and albumin. Subsequently she was moved to MICU on day 2. A paracentesis was performed and ultimately an indwelling catheter was placed for repeat paracentesis. She was placed on doxycycline secondary to persistent leukocytosis. She was downgraded from MICU on day 4 and discharged home in stable condition on day 9.

3 Key Points

  1. OHSS is an iatrogenic disease characterized by enlargement of the ovaries and a fluid shift into the third space
  2. Management primarily revolves around maintaining intravascular volume and adequate urine output
  3. Patients can become critical and require ICU admission due to disease progression, instability, development of ARD, ARF and PE among others.

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