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Ovarian hyperstimulation syndrome

Ovarian hyperstimulation syndrome The Practice Committee of the American Society for Reproductive Medicine American Society for Reproductive Medicine, Birmingham, Alabama This Educational Bulletin discusses the pathophysiology, risk factors, clinical features, and management and pre-vention associated with ovarian hyperstimulation syndrome (OHSS). (Fertil Steril 2008;90:S188–93. 2008 byAmerican Society for Reproductive Medicine.) Ovarian hyperstimulation syndrome (OHSS) is an exagger- effects similar to those of OHSS that can be reversed with ated response to ovulation induction therapy. The OHSS is a specific antiserum ). Recent studies also indicate typically associated with exogenous gonadotropin stimula- that hCG increases VEGF expression in human granulosa tion and is only rarely observed with use of other agents cells and raises serum VEGF concentrations (). Numer- (clomiphene citrate [CC] and gonadotropin-releasing hor- ous other factors may be involved, acting directly or indi- mone [GnRH]). Clinicians who prescribe ovulation-inducing rectly via VEGF, including angiotensin II, insulin-like agents must be prepared to recognize and manage OHSS growth factor 1 (IGF-1), epidermal growth factor (EGF), transforming growth factors (TGF) a and b, basic broblastgrowth factor (BFGF), platelet-derived growth factor OHSS is a self-limiting disorder that usually resolves spon- (PDGF), interleukin-1b (IL-1b), and interleukin-6 (IL-6) taneously within several days, but may persist for longer du- rations, particularly in conception cycles. The syndrome hasa broad spectrum of clinical manifestations, from mild illnessneeding only careful observation to severe disease requiring hospitalization and intensive care. This guideline will discuss The following factors increase the risk independently for the pathophysiology of OHSS and its risk factors, clinical developing OHSS ): features, management, and prevention.
 young age low body weight  polycystic ovary syndrome (PCOS) The hallmark of OHSS is an increase in capillary permeabil-  higher doses of exogenous gonadotropins ity resulting in a fluid shift from the intravascular space to  high absolute or rapidly rising serum E2 levels third space compartments (Factors that have been im-  previous episodes of OHSS plicated in the process include: In addition, risk rises with the number of developing ovar-  increased secretion or exudation of protein-rich fluid ian follicles (and the number of oocytes retrieved in from enlarged ovaries or peritoneal surfaces () assisted reproductive technology (ART) cycles (  increased follicular fluid levels of prorenin and renin Risk increases when higher or repeated doses of exogenous hCG are administered in superovulation and ART cycles  angiotensin-mediated changes in capillary permeability (for ovulation induction or luteal phase support) and decreases when exogenous P, rather than hCG, is used to sup- Vascular endothelial growth factor (VEGF), also known as port the luteal phase ). Pregnancy increases the likelihood, vascular permeability factor, has emerged as one of the fac- duration, and severity of OHSS symptoms.
tors most likely involved in the pathophysiology of OHSS). VEGF is an angiogenic cytokine that is a potent stimu-lator of the vascular endothelium and appears to play an inte- CLINICAL FEATURES gral role in follicular growth, corpus luteum function, and The OHSS has traditionally been classified as mild, moder- ovarian angiogenesis. The VEGF levels correlate with the ate, or severe. However, the clinical symptoms and signs of severity of OHSS (and recombinant VEGF produces OHSS exhibit a continuum of scope and severity that de-fies attempts at specific classification or staging.
Educational Bulletin Mild manifestations of OHSS are relatively common and Reviewed June 2008.
Received July 14, 2003; revised and accepted July 14, 2003.
No reprints will be available.
 transient lower abdominal discomfort Correspondence to: Practice Committee, American Society for Reproduc- tive Medicine, 1209 Montgomery Highway, Birmingham, Alabama35216.
Fertility and Sterility Vol. 90, Suppl 3, November 2008 Copyright ª2008 American Society for Reproductive Medicine, Published by Elsevier Inc.
 Strenuous physical activity should be avoided as risk of  abdominal distention (observed in up to a third of super- ovarian torsion increases when the ovaries are signifi- ovulation cycles) ( cantly enlarged. Light physical activity should bemaintained to the extent possible. Strict bed rest is un- Onset of symptoms typically occurs soon after ovulation warranted and may increase risk of thromboembolism.
(in superovulation cycles) or after oocyte retrieval in ART  Weight should be recorded daily, as well as the fre- cycles, but it may be delayed.
quency and/or volume of urine output. Weight gain of Progression of illness is recognized when symptoms per- R2 pounds per day or decreasing urinary frequency sist, worsen, or include ascites that may be demonstrated should prompt repeated physical examination, ultra- by increasing abdominal girth or ultrasound evaluation. Seri- sound, and laboratory evaluation to include hematocrit, ous illness exists when pain is accompanied by one or more of electrolytes, and serum creatinine.
 Pregnant patients with OHSS must be monitored very closely because risk of progressing to severe disease is  rapid weight gain particularly high for those further stimulated by rapidly rising serum concentrations of hCG.
 hemodynamic instability (orthostatic hypotension,  In ART cycles, it may be necessary to consider cryopre- serving all embryos and deferring transfer to a subse-  respiratory difficulty (tachypnea) quent cycle after symptoms have completely resolved.
 progressive oliguria Although pregnancy rates in frozen ET cycles are gener-  laboratory abnormalities ally lower than in fresh cycles, this approach may reduce Hypotension results from extravasation of protein-rich the risk for developing severe OHSS without a marked fluid and contraction of the vascular volume, oliguria/anuria decrease in pregnancy rates per cycle from reduced renal perfusion due to decreased vascular vol-ume and/or tense ascites, and pulmonary compromise from an elevated diaphragm and/or hydrothorax. Risk of thrombo- Serious illness requiring hospitalization is relatively uncom- embolism is increased as a result of hemoconcentration, di- mon but by no means rare. Hospitalization may be required minished peripheral blood flow, and inactivity due to based on severity of symptoms, analgesic requirements, abdominal distension and pain. Life-threatening complica- and other social considerations (availability of responsible tions of OHSS include renal failure, adult respiratory distress adult supervision, support, and assistance with child care).
syndrome (ARDS), hemorrhage from ovarian rupture, andthromboembolism ().
Given the scope and severity of symptoms and the poten- tial for complications, most women with OHSS who are se-riously ill merit hospitalization for more careful monitoring and aggressive treatment. No one symptom or sign is an ab- Outpatient Management solute indication, but hospitalization should be considered Patients with mild manifestations of OHSS can be managed when one or more of the following are present: on an outpatient basis. Treatment usually requires only oral  severe abdominal pain or peritoneal signs analgesics and counseling regarding the signs and symptoms  intractable nausea and vomiting that prevents ingestion of progressing illness. Intercourse is best avoided as it may be of food and adequate fluids painful and may increase the risk of ovarian rupture.
 severe oliguria or anuria Treatment of worsening OHSS typically requires anti- emetics and more potent analgesics. Most patients still can  dyspnea or tachypnea be effectively managed and monitored on an outpatient basis,  hypotension (relative to baseline), dizziness, or syncope but they require more careful evaluation including frequent  severe electrolyte imbalance (hyponatremia, hyperkale- physical and ultrasound examinations (to detect increasing ascites), daily weight measurements, and serial laboratory  hemoconcentration determinations of hematocrit, electrolytes, and serum creati-  abnormal liver function tests nine. Careful monitoring is essential and should include at Laboratory findings in women with serious illness result- least daily communication, if not examination, to ensure ing from OHSS include ( that progression to more severe disease is promptly recog-nized.
 hemoconcentration (hematocrit >45%) leukocytosis (white blood cell count >15,000) Recommendations for the outpatient management of  electrolyte imbalances (hyponatremia: sodium <135 persistent and worsening OHSS include: mEq/L; hyperkalemia: potassium >5.0 mEq/L)  Oral fluid intake should be maintained at no less than 1 L  elevated liver enzymes per day; any of the commercially available electrolyte-  decreased creatinine clearance (serum creatinine >1.2; supplemented drinks is preferable to other beverages.
creatinine clearance <50 mL/min) Fertility and Sterility Recommendations for the evaluation and monitoring of  Albumin (25%) in doses of 50–100 g, infused over 4 hospitalized patients with OHSS include the following: hours and repeated at 4- to 12-hour intervals as neces-sary, is an effective plasma expander when infusion of  vital signs (every 2–8 hours, according to clinical status) normal saline fails to achieve or maintain hemodynamic  weight (recorded daily) stability and adequate urine output. In general, albumin  complete physical examination (daily, avoiding biman- is the preferred plasma expander (although others ual examination of the ovaries due to risk of ovarian rup- (e.g., mannitol, fresh frozen plasma) may be used. Dex- tran has been associated with development of adult  abdominal circumference (at the navel, recorded daily) respiratory distress syndrome (ARDS) and is best  monitoring of fluid intake and output (daily, or more of-  Treatment with diuretics (e.g., furosemide, 20 mg IV)  ultrasound examination (ascites, ovarian size), repeated may be considered after an adequate intravascular vol- as necessary to guide management or paracentesis (see ume has been restored (hematocrit <38%). Premature or overzealous use of diuretics will aggravate hypovole-  chest X-ray and echocardiogram (when pleural or peri- mia, and hemoconcentration, thereby increasing risk of cardial effusion is suspected), repeated as necessary  pulse oximetry (for patients with symptoms of pulmo-  Intravenous fluid administration should be sharply curtailed and oral fluid intake increased when there is  complete blood count (daily, or more often as needed to evidence that the syndrome is resolving, generally her- guide fluid management) alded by improving symptoms and onset of a brisk  electrolytes (daily)  serum creatinine or creatinine clearance, urine specific  Hyperkalemia is associated with risk of cardiac dys- gravity, repeated as necessary rhythmias. Acute management involves treatments that  liver enzymes, repeated as necessary move potassium into the intracellular space (insulin Careful and frequent re-evaluation of the hospitalized and glucose, sodium bicarbonate, albuterol) or protect patient with severe OHSS is essential. Complaints of increas- the heart from the effects of elevated potassium levels ing abdominal pain and distension demand immediate atten- (calcium gluconate). Electrocardiographic manifesta- tion, remaining mindful that pain and ascites can easily mask tions of hyperkalemia (prolonged PR and QRS intervals, ovarian rupture and acute intra-abdominal hemorrhage. Serial ST segment depression, tall peaked T waves) indicate clinical and laboratory evaluations provide the means to mon- the need for immediate treatment with calcium gluco- itor progression of illness, to judge the response to treatment, nate. Kayexelate is a cation exchange resin that removes and to recognize evidence of resolution.
potassium from the body but works more slowly (onsetof action 1–2 hours); it may be administered orally orrectally as a retention enema.
Hospitalized patients require IV fluid management to addressthe acute need for volume expansion while also considering the marked increase in vascular permeability that accom- Ultrasound-guided paracentesis may be indicated for patients panies severe OHSS. Renal and pulmonary function must with ascites that causes pain, compromised pulmonary func- be carefully monitored. Guidelines for fluid management tion (e.g., tachypnea, hypoxia, hydrothorax) (or oliguria/ for patients hospitalized with severe illness relating to anuria that does not improve with appropriate fluid manage- OHSS include the following ( ment. A transvaginal or transabdominal approach may be  Strict monitoring of fluid intake and urine output is used, under gentle ultrasound guidance (The optimal essential until symptoms improve or diuresis begins.
volume of fluid that should be removed on any one occasion,  Oral fluid intake should be carefully recorded and lim- and over what interval of time, is not well established.
ited to those amounts necessary to maintain the patient's Whereas rapid removal of large volumes of ascitic fluid has been observed to trigger dangerous compensatory fluid shifts  Rapid initial hydration may be accomplished with a bo- in elderly patients with malignant ascites, the risk of such lus of IV fluid (500–1,000 mL). Thereafter, fluids should complications in young, otherwise healthy women with be administered judiciously, in the volumes necessary to OHSS is generally small. Nevertheless, it is prudent to re- maintain adequate urine output (>20–30 mL/h) and move fluid at a deliberate pace until the desired effect is reverse hemoconcentration. Five percent dextrose in achieved, while carefully monitoring the patient's response.
normal saline is preferable to lactated Ringer's solution, Serial paracentesis may be required to maintain adequate re- given the tendency to hyponatremia. Correction of hy- nal and pulmonary function. Severe ascites may be associated povolemia, hypotension, and oliguria has highest prior- with hydrothorax, most commonly on the right, resulting ity, accepting that fluid administration may contribute to from transfer of abdominal fluid to the chest via the thoracic the accumulation of ascites.
duct. Paracentesis will generally be effective in resolving ASRM Practice Committee Ovarian hyperstimulation syndrome Vol. 90, Suppl 3, November 2008 hydrothorax and thoracentesis may be reserved for those with LH surge to promote final oocyte maturation and induce bilateral or severe pleural effusions that persist ().
ovulation ). This approach would be useful only in cyclesnot involving previous down-regulation with longer term ag- Thromboembolism is a life-threatening complication of onist treatment or use of a GnRH antagonist (e.g., ganirelix, severe OHSS, and prophylactic measures are warranted.
Full-length venous support stockings are recommended, andprophylactic heparin therapy (5,000 U SC, every 12 hours) Regardless whether hCG or a GnRH agonist is adminis- should be seriously considered. The use of an intermittent tered at midcycle, the use of exogenous P (e.g., 50 mg P in pneumatic compression device is prudent when symptoms oil IM, 100 mg P vaginal suppositories, or 8% P vaginal prevent ambulation and confine the patient to bed. Signs gel, daily) for luteal phase support rather than supplemental and symptoms suggesting thromboembolism demand prompt doses of hCG, may further reduce risks of OHSS ( additional diagnostic measures (arterial blood gas measure- When symptoms of OHSS emerge even before administra- ments, ventilation/perfusion scan) and therapeutic anticoagu- tion of hCG, cycle cancellation and less aggressive stimula- lation when the diagnosis is confirmed or strongly suspected.
tion in a subsequent cycle should be seriously considered.
Intensive care may be required for management of Although evidence indicates that meticulous follicle aspi- thromboembolic complications, renal failure, or pulmonary ration will reduce corpus luteum P production, it cannot be compromise that does not respond to supportive care and relied on to prevent development or progression of OHSS paracentesis. Renal failure will often respond to low-dose do- in ART cycles ).
pamine therapy (0.18 mg/kg/h) that will dilate renal vessels Prophylactic IV administration of 25% albumin (20–50 g) and increase renal blood flow ). Invasive monitoring of at time of oocyte retrieval has been suggested as a means to central venous pressure or pulmonary capillary wedge pres- reduce risk of OHSS when E sure and even short-term dialysis may be required. Pulmo- 2 levels are markedly elevated or there is history of a previous episode of OHSS nary intensive care may involve oxygen supplementation, Studies of its efficacy have had mixed results, and albumin thoracentesis, and assisted ventilation when more conserva- treatment risks exacerbation of ascites, allergic reactions, tive measures fail. Patients with severe OHSS who may re- and virus/prion transmission (However, a recent quire surgery for a ruptured ovarian cyst with hemorrhage, meta-analysis of five randomized controlled trials demon- torsion, or an ectopic pregnancy present a unique challenge strated that prophylactic albumin administration significantly for the anesthesiologist who is unlikely to be familiar with reduced risk of developing OHSS (odds ratio [OR] 0.28, 95% the pathophysiology of the syndrome and must be quickly ed- confidence interval [CI] 0.11, 0.73); albumin infusion may be ucated to minimize the additional risks involved ).
expected to prevent one case of severe OHSS for every 18women at risk who are treated ).
The keys to preventing OHSS are experience with ovulationinduction therapy and recognition of risk factors for OHSS.
Ovulation induction regimens should be highly individual-  Experience with ovulation induction therapy and knowl- ized, carefully monitored, and use the minimum dose and du- edge of OHSS pathophysiology, risk factors, and clini- ration of gonadotropin therapy necessary to achieve the cal features are key to preventing and managing OHSS.
therapeutic goal.
 Mild manifestations of OHSS are fairly common, occur- ring in up to a third of exogenous gonadotropin-induced Caution is indicated when any of the following indicators for increasing risk of OHSS are present:  Worsening symptoms of OHSS can still usually be man-  rapidly rising serum E2 levels aged on an outpatient basis, but frequent monitoring and  an E2 concentration in excess of 2,500 pg/mL evaluation are essential.
 the emergence of a large number of intermediate sized  Serious illness resulting from OHSS is much less com- follicles (10–14 mm) mon, but it can be life-threatening.
 Hospitalization may be necessary for patients with seri- Withholding further gonadotropin stimulation and delaying ous illness resulting from OHSS.
hCG administration until E2 levels plateau or decrease signif-icantly can reduce risks of OHSS Available evidencesuggests that such ‘‘coasting'' does not adversely affect out-come in IVF cycles unless it is prolonged (>3 days) ).
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ing severe ovarian hyperstimulation syndrome. Cochrane Database Syst Intravenous albumin for the prevention of severe ovarian hyperstimula- Fertility and Sterility


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7th Workshop on Recent Issues in Bioanalysis Poster List Tuesday April 9 Posters Poster T01: "Validation of a Dried Blood Spot Boanalytical Method for Perampanel Analysis in Pediatric Studies" Poster Presenter: Dr. Luca Matassa (Eisai, Woodcliff Lake, NJ, USA) Introduction: Perampanel is a first-in-class, orally administered, highly selective non-competitive AMPA-type glutamate receptor antagonist, developed by EISAI for epilepsy. A DBS-LC-MS/MS method has been developed and validated in order to analyse perampanel in heparinised blood samples from paediatric studies. Dried blood spots (DBS) have been shown to be a useful means of collecting, storing and shipping blood samples for quantitative drug analysis which provides advantages over conventional plasma collection. Moreover, due to low sample volume that DBS uses, it is a method of choice when it is comes to paediatric studies. Methods: A 20 uL dried blood spot on FTA DMPK A card is punched (6mm punch) and the subsample is solubilized by shaking in 150 uL of 90/10 methanol water containing internal standard (IS) stable label peramapanel. An aliquot of the solution is diluted with an equal volume of 50/50 methanol/water, centrifuged at 4C for 5 min prior to injecting 10uL on a reverse phase column (Chromolith RP18e 100x3mm) at 40C under gradient conditions. The detector was a Sciex API5500 Qtrap operated in positive ion ionspray mode. Quantitation was achieved monitoring precursor/product ions for analyte and IS (350/219 m/z perampanel; 356/219 IS) at retention time 2.5 minutes using 1/x2 linear weighted regression. Result: A full validation according to FDA and EMA guidance was conducted in human blood. Assay linearity was demonstrated over 7 validation runs with R-squared greater than 0.995. The intra-run accuracy and precision was between 95.2 -107.6% and 3.1-12.6%, respectively, at four concentration levels (LLQ, low QC, mid QC, high QC) demonstrating the repeatability of the analytical method from 1 to 500 ng/mL. The matrix factor in 6 lots of control blood was 1.0 for analyte and IS. Control blank matrix showed no interference at the LLQ. Punch tool carryover and autoinjector carryover were not found to impact assay performance. Analyte and IS recovery was 80% across all 3 QC levels with imprecision less than 5%. A 2-fold dilution factor was validated. The specificity of the method for perampanel at the LLOQ in presence of 10 other commonly used AEDs, individual y or pooled all together, (valproic acid, phenobarbital, lamotrigine, topiramate, oxcarbazepine, carbamazepine, levetiracetam, zonisamide, phenytoin, primidone) was demonstrated. A blood/plasma ratio of 0.88 was determined, allowing the correlation between blood and previous study plasma results. Short term autosample perampanel extract stability and perampanel stability in blood was demonstrated. Perampanel long term stability on DBS was demonstrated for 363 days at room temperature. Novel Aspect / Conclusion: The fully validated DBS-LC-MS/MS method was successfully applied to analysis of paediatric study clinical samples. Poster T02: "Unexpected Results for Sample Col ection and Handling Stability Assessment for Sumatriptan in Human Plasma" Poster Presenter: Ginny James (Celerion, Lincoln, Nebraska, USA) Introduction: Determination of sample col ection and handling stability (SCHS) is a requirement for validation of bioanalytical methods. SCHS of sumatriptan for 120 minutes did not meet pre-defined acceptance criteria. As sumatriptan was stable in plasma for 23 hours at ambient temperature, it was hypothesized that partitioning of sumatriptan between plasma and red blood cells was not immediate and was impacting the results of the early time points. Methods: Whole blood was fortified with sumatriptan at 0.150 and 100 ng/mL for target plasma concentrations of approximately 0.300 and 200 ng/mL. The samples were incubated in an ice-water bath, at ambient temperature, and at 37°C for multiple time points between 0 and 120 minutes. At each time point, samples were centrifuged, and the plasma layer was immediately frozen at -20°C. For samples in an ice-water bath for 30 minutes, the red cell fraction was also stored at -20°C for testing. The collected plasma samples were analyzed using a validated method for the quantitation of sumatriptan in human plasma. Red blood cel s were analyzed with the same chromatographic and instrument conditions after a protein crash of the cellular material.

CURRENT DRUG THERAPY EDUCATIONAL OBJECTIVE: Readers will prescribe antidepressant drugs more confidently on the basis CREDIT of the characteristics of the patient and the various drugs ELIZABETH SHULTZ, DO DONALD A. MALONE, JR., MD Department of Psychiatry and Psychology, Chair, Department of Psychiatry and Psychology, Cleveland Clinic; Clinical Instructor, Cleveland Cleveland Clinic; Professor, Cleveland Clinic Lerner