Case Part 2

On initial examination, she appears to be comfortable overall. Vital signs are signi - cant for heart rate of 105 bpm, blood pressure of 90/60, and weight of 141 pounds (reports baseline weight of 133–135 pounds). Her lungs are clear to auscultation bilaterally. On abdominal exam, she is noted to have moderate distension with mild tenderness to palpation in the lower quadrants and suprapubic region. A fuid wave is also noted. Lower extremity exam is unremarkable. Laboratory evaluation is signi cant for a hematocrit of 47%, sodium of 136 mEq/L, and creatinine of 1.1 mg/ dL. A quantitative serum hCG is 220 mIU/mL. Pelvic sonogram reveals marked bilateral enlargement of the ovaries with the right and left ovary measuring 10.2 × 9.1 × 9.2 cm and 9.8 × 6.5 × 5.4 cm, respectively, and moderate free fuid in the anterior and posterior cul-de-sacs.

Discussion

Ovarian hyperstimulation syndrome (OHSS) is an iatrogenic complication associated with controlled ovarian hyperstimulation (COH) during assisted reproductive technology (ART) treatment. Though rare (incidence ranges from 0.1 to 5% of all ART cycles depending on treatment type), it a serious and potentially life-­threatening condition that requires diligent diagnosis and management. It can occur in all ART clinical settings—oral ovulation induction with clomiphene citrate or aromatase inhibitors (incidence of moderate to severe disease is very low), ovulation induction with exogenous gonadotropins, or in vitro fertilization (IVF). Symptoms include ovarian enlargement, ascites, hemoconcentration, hypercoagulability, and electrolyte abnormalities that are classi ed by their severity as seen in the table below. In its most severe form, OHSS can lead to serious complications including pleural effusion, acute renal insuf ciency, and venous thromboembolism. Symptom presentation is usually described as either early: typically 3–7 days after ovulatory trigger and mediated by exogenous hCG or late: typically at least 9 days after trigger administration and mediated by endogenous hCG due to pregnancy.

The pathophysiology of OHSS involves the sequalae of ovarian enlargement and increased vascular permeability. Increased arteriolar vasodilation and increased capillary permeability leads to third spacing of fuid from intrato extra-vascular spaces. This fuid shift leads to intravascular hypovolemia in the setting of fuid overload which explains the clinical and laboratory ndings seen on initial presentation. Vascular permeability is thought to be mediated by several vasoactive factors secreted by the enlarged ovary, with vascular endothelial growth factor (VEGF) playing the central role. VEGF acts directly on endothelial cells to induce proliferation and angiogenesis and is involved in follicular growth and corpus luteum

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Adapted from the Practice Committee of the American Society for Reproductive Medicine. Prevention and treatment of moderate and severe OHSS. Fertil Steril 2016

Because there is no speci c treatment for OHSS, identifying patients at risk is key to lowering its incidence. Prevention strategies should begin prior to treatment with protocols tailored to each patient’s individual parameters. Medication dosages should be based on an individual’s age, BMI, ovarian reserve, and prior stimulation history, with lower doses used for those patients considered at higher risk for development of symptoms. In IVF, GnRH antagonist protocols are associated with a lower incidence of OHSS as compared to GnRH agonist protocols regardless of trigger type. Incorporating a GnRH antagonist into IVF protocols allows for the use of a GnRH agonist trigger, which has been shown to signi cantly reduce the incidence of OHSS. Once stimulation has begun, other strategies that can be used to lower the risk of OHSS are step-down protocols (lowering of gonadotropin doses as follicle sizes increase) and coasting (withholding of gonadotropins for up to 4 days). Because hCG is so highly associated with the development of OHSS, withholding hCG and cycle cancelation may be the only option for those patients deemed at very high risk for OHSS.

Choice of trigger for nal oocyte maturation is also crucial for prevention of OHSS. The use of hCG for trigger was once standard of care; however, the long half-life of hCG leads to sustained LH-like activity and stimulation of the ovaries post-retrieval, thereby increasing the risk of OHSS. Modifying the dose of hCG to doses lower than the standard 10,000 IU (2500–5000) has been shown to lead to adequate oocyte maturity with lower risk of OHSS. Dose adjustment should be done according to patient estradiol level and BMI. GnRH agonist trigger (2–8 mg Leuprolide acetate) induces endogenous LH release, which has a much shorter half-­ life than hCG and as such, signi cantly reduces the incidence of both early and late forms of OHSS when used either alone or in conjunction with a much lower dose of hCG (~1500 IU). Because of LH’s shorter half-life, luteolysis occurs early and luteal support with both estradiol and progesterone are required. It is important to remember that a GnRH agonist trigger can only be utilized in GnRH antagonist cycles, as GnRH agonist downregulated patients will not respond to an agonist trigger. Furthermore, even in the setting of antagonist cycles, a small subset of patients (~5%) will fail to elicit an adequate LH response to the GnRH agonist trigger. Identifying these risk factors (history of hypothalamic amenorrhea, LH levels <0.1 at cycle start or day of trigger, long-term OCP use) prior to trigger selection is critically important.

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•\ Electrolyte abnormalities (Na <125 mEq/L, K >5 mEq/L). •\ Decreased creatinine clearance (Cr >1.2 mg/dL).

•\ Elevated liver enzymes.

Hospitalized patients require frequent monitoring of vital signs, body weights and abdominal circumferences, intake and output (I&Os), serial lab evaluations, and imaging as indicated (i.e., chest X-ray if shortness of breath). Fluid management is critical and normal saline is preferred over lactated ringers given the often-­ observed hyponatremia/hyperkalemia. For those patients with intractable nausea/ vomiting and/or pain, adequate doses of analgesics and/or anti-emetics should be provided. Pregnant women should also receive any necessary luteal support with progesterone. All hospitalized patients should receive prophylactic anticoagulation and wear lower extremity sequential compression devices while in bed. Ultrasound-­ guided paracentesis may be indicated for patients with ascites that causes pain, compromised pulmonary function, or oliguria/anuria that does not improve with appropriate fuid management. Both transvaginal and transabdominal approaches can be used depending on provider preference. While the absolute volume of fuid to be removed via paracentesis is not well established, fuid should be removed slowly, while carefully monitoring patient’s response. Volume expanders such as albumin are often given in conjunction with paracentesis although the data regarding their ef cacy is limited. Serial paracentesis may be required to maintain adequate renal and pulmonary function. Management in an intensive care unit maybe necessary for patients with thromboembolic complications, renal failure, or pulmonary compromise not responsive to supportive care and paracentesis.

Case Part 3

The patient was admitted to the hospital for management of her OHSS. She was initially given a bolus of 1 L of normal saline and then maintained at 125 cc/h. A foley catheter was placed to monitor urine output. She was also started on 5000 iu of subcutaneous heparin twice daily for DVT prophylaxis. After being started on anti-emetics, she was able to tolerate small amounts of food/drink orally. After some initial symptom relief and slight improvement in labs and urine output, she was noted to have worsening abdominal distension and discomfort on hospital day 3. Labs showed improvement in hemoconcentration (Hct 43%) but an increase in her creatinine (1.4). Urine output has also decreased to <20 cc/h. Given her deteriorating renal function and discomfort, she underwent an ultrasound-guided transabdominal paracentesis performed at interventional radiology. A total of 1.5 L of ascitic fuid was removed and renal function improved dramatically over the next 24 h. By hospital day 5, she reported signi cant improvement in symptoms—she was only mildly distended and was tolerating a regular diet. Electrolytes and creatinine were all within normal range and hematocrit was stable at 44%. Her hCG level was monitored and continued to rise appropriately throughout her stay. She was discharged to home on hospital day 7 with a plan for close outpatient follow-up by her local reproductive endocrinologist.

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