Joseph G. Whelan III, M.D., and Nikos F. Vlahos, M.D.

Transcription

1 FERTILITY AND STERILITY VOL. 73, NO. 5, MAY 2000 Copyright 2000 American Society for Reproductive Medicine Published by Elsevier Science Inc. Printed on acid-free paper in U.S.A. MODERN TRENDS The ovarian hyperstimulation syndrome Joseph G. Whelan III, M.D., and Nikos F. Vlahos, M.D. Department of Gynecology and Obstetrics, The Johns Hopkins University School of Medicine, Baltimore, Maryland Objective: To review the up-to-date literature concerning the pathogenesis of, risk factors for, prevention of, and therapy for the ovarian hyperstimulation syndrome, and to provide suggestions for management of this syndrome. Design: Literature review combined with on-site clinical experiences at the authors institution of practice. Patient(s): Women who have risk factors for or manifest the ovarian hyperstimulation syndrome. Intervention(s): Intravenous fluid management, thrombosis prevention techniques, paracentesis techniques, and critical care management protocols. Main Outcome Measure(s): Staging system of the ovarian hyperstimulation syndrome, criteria for outpatient versus hospitalization management, and indications for varying levels of interventional management. Result(s): The ovarian hyperstimulation syndrome, unique to the field of assisted reproductive technology, remains a largely elusive and unpredictable iatrogenic physiologic complication in the course of pharmacologic ovarian stimulation. Reliable information on risk factors, possible physiologic mechanisms, prevention techniques, and management is fortunately progressing, and overall advances are being made in this field. The present review is an attempt to summarize the modern literature regarding this syndrome and to use this current knowledge to provide a basis for acceptable management regimens. Conclusion(s): Ovarian hyperstimulation syndrome is a serious complication of assisted reproductive technology, with potential for critical morbidity and death. Physicians who prescribe medications known to be associated with this syndrome should be familiar with identifiable risk factors, means of prevention, and a system for staging and treating the disease and have a current knowledge base for putative models of pathogenesis. (Fertil Steril 2000;73: by American Society for Reproductive Medicine.) Key Words: Ovarian hyperstimulation syndrome, controlled ovarian hyperstimulation, assisted reproductive technologies, polycystic ovarian syndrome, in vitro fertilization, ovulation induction, paracentesis Received January 13, 2000; accepted January 13, Reprint requests: Joseph G. Whelan III, M.D., Department of Gynecology and Obstetrics, The Johns Hopkins University School of Medicine, 600 North Wolfe Street, Phipps 249, Baltimore, Maryland (FAX: ) /00/$20.00 PII S (00)00491-X The ovarian hyperstimulation syndrome (OHSS) is a serious and potentially life-threatening physiologic complication, classically encountered in patients who undergo controlled ovarian hyperstimulation (COH) cycles. The syndrome is typically associated with regimens of exogenous gonadotropins but also can be seen, albeit rarely, during administration of clomiphene citrate for ovulation induction. Although the full manifestation of the syndrome occurs in the postovulatory (or post oocyte retrieval) phase of a stimulated cycle, signs and symptoms predictive of OHSS can be seen earlier in the stimulation phase of the cycle. Ovaries enlarge, capillary permeability increases, and protein-rich fluid leaves the intravascular space. This results in hemoconcentration, third-space edema, and, in severe cases, accumulation of ascites in such body cavities as the abdomen, pleural space, or pericardial space. Physical symptoms usually begin with a sensation of abdominal bloating, then proceed to nausea, vomiting, and diarrhea. They may progress to lethargy and complete loss of appetite. Shortness of breath and/or a history of decreased urine output are particularly ominous symptoms of significant morbidity, as they may represent accumulation of ascites. Clinical signs may include any or all of the following: rapid weight gain, oliguria or anuria, hemoconcentration, leukocytosis, hypovolemia, electrolyte imbalance (typically hyponatremia and hyperkalemia), ascites, pleural and pericardial effusions, the adult respiratory distress syndrome (ARDS), hypercoagulability with thromboembolic sequelae, and multiple organ failure. Deaths related to OHSS are known to occur (1); however, documen- 883

2 TABLE 1 OHSS classification. OHSS Stage Grade Mild Moderate Severe 1 Abdominal distension/discomfort 2 Features of grade 1 plus nausea, vomiting, and/or diarrhea Ovaries enlarged to 5 12 cm 3 Features of mild OHSS plus ultrasonographic evidence of ascites 4 Features of moderate OHSS plus clinical evidence of ascites and/or hydrothorax or difficulty in breathing 5 All of the above plus change in blood volume, increased blood viscosity due to hemoconcentration, coagulation abnormalities, and diminished renal perfusion and function Note: Based on the system of Golan and colleagues (3). OHSS ovarian hyperstimulation syndrome. Whelan. Ovarian hyperstimulation syndrome. Fertil Steril tation is unfortunately scant regarding these incidents. NATURAL COURSE OF DISEASE The ovarian hyperstimulation syndrome should be uniformly self-limiting. Regression takes place spontaneously over days as long as prompt and appropriate supportive care is provided to avoid deterioration of the patient s condition. Clinical resolution seems to parallel the decrease of residual exogenous serum levels of human chorionic gonadotropin (hcg) after an oocyte-maturation dose at the culmination of a COH cycle. Consequently, a pregnancy implantation (whether intrauterine or not) with a subsequent increase in endogenous hcg may prolong or worsen a current episode of OHSS or initiate a late form of OHSS (2). CLINICAL STAGING SYSTEM The most popular classification system for staging OHSS is that of Golan et al. (3). This system encorporates clinical signs, symptoms, ultrasonographic findings, and laboratory findings to yield three levels and five grades of OHSS severity (Table 1). For practitioners who have significant experience with COH cycles, it should come as no surprise that a large percentage of patients undergoing COH may develop symptoms of grade 1 OHSS by Golan s classification. Indeed, the incidence of OHSS in patients undergoing COH has been reported to be as high as 33% using this classification (3). This frequent finding should serve as a reminder that the manifestations of OHSS occur within a spectrum, and preventive measures instituted at an early stage may be the best way to avoid severe morbidity. One criticism of the Golan classification system is that within the level of severe, there is no distinction regarding which patients may be in an imminently life-threatening condition (4). In our opinion, all cases of severe OHSS determined by using the Golan classification should be regarded as potentially critical and require hospitalization. PATHOPHYSIOLOGY The cardinal event in the genesis of morbidity associated with OHSS appears to be increased capillary permeability (5, 6) resulting in an intravascular fluid shift to the third space compartments during ovarian hyperstimulation. A great deal of attention has been directed toward the possible implication of the ovarian renin-angiotensin system in the pathophysiology of OHSS. Prorenin (PR) and active renin (R) are synthesized in human ovarian theca cells (7). Human menopausal gonadotropins (hmg) and hcg have been shown to induce R activity in follicular fluid (8) and to stimulate ovarian PR production (9, 10). Follicular fluid from women undergoing COH has been shown to contain not only PR and R but also angiotensin-converting enzyme (ACE) (11), angiotensin I, angiotensin II, and angiotensinogen (9). Angiotensin II has been shown to regulate vascular wall permeability (12) and to affect ovarian steroidogenesis in association with ovarian renin activity (8). Although human studies have shown high plasma levels of total R corresponding to the degree of OHSS (13, 14) and blockade of ACE has diminished OHSS manifestation in the rabbit model (15), the ovarian reninangiotensin system has failed thus far to be accepted as the authentic and complete physiologic model for this syndrome. Systemic and local (i.e., ovarian) inflammatory processes 884 Whelan and Vlahos The ovarian hyperstimulation syndrome Vol. 73, No. 5, May 2000

3 involving such mediators as cytokines (16, 17), histamine (18 20), prostaglandins (21, 22), and vascular endothelial growth factor (VEGF) (23 27) have been studied to provide a physiologic model for this syndrome. Among these factors, VEGF seems to be the most convincing as an integral mediator in OHSS. Vascular endothelial growth factor is a vasoactive glycoprotein also sometimes referred to as vascular permeability (VPF) factor. This endothelial-cell growth factor is known to stimulate endothelial-cell proliferation and angiogenesis (27). Evidence that VEGF is in fact a mediator of ovarian origin has come from the finding that VEGF messenger RNA is expressed in luteinized granulosa cells in vitro (28, 29). The impressive work by Levin et al. (27) has revealed that VEGF is not only correlated with OHSS but also seems to correlate directly with the degree of disease. Endothelial-cell permeability was shown to increase after exposure to follicular fluid containing VEGF. This effect was dose related, as the permeability of endothelial cells exposed to follicular fluid showed a direct and linear relation when the follicular fluid was retrieved from ovaries with greater numbers of oocytes. Antibody to VEGF reverses this effect in vitro. The ability of VEGF to cause increased endothelial cell permeability is mediated in part by nitric oxide and inhibition of nitric oxide was shown to reverse this increased permeability. These findings further implicate VEGF specifically as a follicular fluid agent capable of inducing in vivo endothelial-cell permeability with subsequent intravascular fluid loss into third space tissues and cavities. In terms of a cellular-level mechanism, incubation of endothelial cells with VEGF was shown to induce changes in cellular actin fibers, which could compromise the maintenance of tight cell junctions. Demonstration of VEGF mrna from human granulosa cells has also been correlated with hcg in a dose- and time-dependent manner (29). Since hcg is used to trigger oocyte maturation in ovarian stimulation cycles and manifestations of OHSS occur within a predictable time frame in the presence of hcg, it seems convincing that the administration of hcg at the culmination of a COH cycle may be the key event in the induction of OHSS via a mechanism mediated by VEGF. Confounding to many theories about the pathogenesis of OHSS is the frequent absence of the syndrome in some patients who would seem to be at greatest risk. It is of interest in this regard that variable levels of granulosa cell VEGF mrna expression have been noted among individual patients undergoing COH (28), perhaps elucidating the sporadic incidence of the disease. Thromboembolism can occur in association with OHSS and should be respected for its potentially grave morbidity; however, it may not necessarily be an integral mechanism of the syndrome. Increased monocyte tissue factor expression has been associated with OHSS (30). Interestingly, von Willebrand factor (vwf) has been proposed as an endothelial marker for OHSS (31), and excessive endothelial cell VEGF production enhances vwf serum concentrations (32). However, hyperestrogenic states can induce hypercoagulability by affecting coagulation and fibrinolytic factors. Hemoconcentration-related leukocytosis (leukocyte count of 22,000 cells/mm 3 ) and fibrinolytic system activation have been reported as ominous signs for imminent thromboembolism in an OHSS patient (33). Activation of the coagulation cascade and fibrinolytic system has been shown to take place several days after administration of hcg (34). Thus, the manifestation of thrombosis in OHSS may more likely represent a consequence of hyperestrogenemia, hemoconcentration, and presence of hcg rather than an intrinsic aspect of the syndrome s pathophysiology. Although ovarian enlargement is seen uniformly in OHSS, the significance of this change in the pathogenesis of OHSS is not conclusive. In our experience, ovaries that are hyperstimulated as a result of gonadotropin treatment in which aspiration is not performed tend to be larger than ovaries that have been aspirated for IVF purposes. Nevertheless, recording measurements of ovarian size is not currently considered useful as a prognostic indicator nor as an indicator of the stage of disease. RISK FACTORS Young age, low body weight (35, 36), certain protocols for COH (37 39), high estradiol levels (36, 40), rapidly increasing estradiol levels (36, 41), size and number of stimulated follicles (41, 42), number of oocytes retrieved (41), and evidence of the polycystic ovarian syndrome (35, 43, 44) have all been found to be risk factors associated with the development of OHSS. Most of these purported risk factors have been regarded as at least debatable in follow-up studies. There appears to be general recognition that patients with a history of OHSS are at risk for recurrence in subsequent COH cycles. Young age would seem to be a logical risk factor, since these patients have a larger number of recruitable follicles and a higher density of gonadotropin receptors, thus rendering them more responsive to gonadotropins. Lean body weight and body mass index, however, have been found to be unreliable as OHSS risk factors (45). Many comparative studies have assessed the components of stimulation protocols and associated risk of OHSS. Results vary widely and probably are most dependent on the patient profiles being evaluated. Most of these studies do, however, find two common clinical correlations: the association of exogenous hcg with the development of OHSS and the apparent preventive nature of using progesterone instead of hcg for luteal phase support. The use of injectable hcg FERTILITY & STERILITY 885

4 has been shown to be significantly correlated with development of OHSS when administered in a COH cycle to mature oocytes before retrieval and provides luteal phase support (46). Progestogens have been associated with a lesser incidence of OHSS when used for luteal phase support (37) and are therefore recommended for this purpose in high-risk COH cycles. Although estradiol level, follicular size, and number and quantity of oocytes retrieved have all been independently implicated as risk factors for OHSS, the significance of these variables is probably more a consequence of the high physiologic level at which the ovary is functioning. While the hyperestrogenemic state may contribute to the hypercoagulability and thrombogenic sequelae seen in OHSS, the role of an elevated estradiol level, or other hormone levels that increase in OHSS (47), as an independent risk factor for development of the syndrome remains uncertain. The arbitrary level of serum estradiol above which one could be considered at high risk for OHSS is debatable (48, 49). There are obviously other mediators that may give rise to the syndrome, since many COH patients become hyperestrogenemic but do not develop OHSS. A patient profile consistent with PCOS especially a necklace appearance of the ovaries on ultrasonography has generally been found to be a predictable risk factor for OHSS. Once a precise physiologic model for OHSS is determined, the facilitative role of PCOS should be more lucid. More simply, it would seem that patients with a large pool of antral follicles at the outset of a COH cycle would be prone to developing OHSS should all of those follicles be stimulated to excessive physiologic function. In a recent prospective cohort study assessing risk factors for OHSS at the outset of COH cycles, a history of allergy was identified in 50% of the patients who ultimately developed severe OHSS (41). Mast cells have been found to be more inducible, reactive, and abundant in the mucous membranes of allergic persons (50). Since animal studies have revealed large numbers of mast cells in dominant follicles, which appear to cycle with ovulation (51), an association between innate systemic immunologic hypersensitivity and development of OHSS seems feasible. Unfortunately, the prospective cohort study was not blinded. Furthermore, the patients allergies were assessed by history only and were not documented objectively. Also of note in this study is that luteal phase support was accomplished with serial subcutaneous injections of hcg. In regard to allergy or hypersensitivity as a risk factor for OHSS, the literature contains some interesting findings involving histamine and histamine blockade. In a provocative controlled study, Knox et al. (18) showed that histamine blockade could prevent manifestation of OHSS in a rabbit model, then later demonstrated that the hmg-induced state of OHSS in the rabbit model did not involve peripheral antigen antibody complexes (19). The latter finding leaves open the possibility that the antihistamine blockade of the development of OHSS in the rabbit model is taking place at the level of the ovary. Later studies using the rabbit model showed that antihistamine treatment caused a statistically significant faster regression of OHSS compared with controls (20, 52). Another study using a rabbit model, however, showed no difference in either histamine levels or ovarian mast-cell content between OHSS groups and controls (53). PREVENTION The fact that OHSS is essentially an iatrogenic complication of assisted reproductive technology is of particular importance from a liability standpoint, since the sole responsibility for the condition lies in the hands of the practitioner(s) who initiated the ovarian stimulation cycle. It is therefore obligatory that those who prescribe medications for follicular hyperstimulation be familiar with methods that can prevent OHSS as well as with measures to take once OHSS becomes evident. Recognizing the OHSS high-risk profile is probably the most important measure of prevention the physician can take before beginning any COH cycle or ovulation induction. Of the variables reviewed in the Risk Factors section, young age and evidence of PCOS are perhaps the most valuable, as these factors can be assessed before administering medications. Once a high-risk clinical profile is established, the next step should be to individualize the patient s medication regimen. Stimulation medications (gonadotropins or clomiphene) should be started at the lowest standard dose, then followed by close monitoring of serum estradiol level and follicle imaging to plan for a step-up medication regimen as deemed necessary by the results of monitoring. Various recommendations have been proposed regarding the duration of precycle GnRH agonist suppression and the time frame of its use within a COH cycle to lessen the risk for OHSS. It has been our experience, however, that GnRH agonist suppression confers a risk for OHSS on the patient regardless of how it is used. We do not deviate from our standard GnRH agonist suppression protocols for patients with a high-risk profile. The regimen of GnRH agonist suppression may be abbreviated if the patient has a history of oversuppression or has less ovarian reserve but not necessarily for those with a history of PCOS or other OHSS risk factors. Myriad studies have assessed the inherent risks for OHSS relative to all of the individual stimulation medications currently available, represented in diverse proposed COH regimens. Even though many of these studies are well designed and have yielded persuasive data, it is generally acknowledged that any of the stimulation medications currently available can induce OHSS, and none can claim impunity. Having an appreciation for the patient clinical profile and individualizing COH regimens with close monitoring in 886 Whelan and Vlahos The ovarian hyperstimulation syndrome Vol. 73, No. 5, May 2000

5 high-risk situations will be more effective prevention than relying on any particular medication regimen purported to less likely result in OHSS. In addition to a complete physical and pelvic examination, baseline ultrasonography of the uterus and ovaries and assessment of estradiol and gonadotropins are done before initiating a COH cycle at our institution. Following a standard GnRH agonist suppression regimen, stimulation medications (FSH or LH or both, depending on the individual case) are begun at relatively low dosages for patients considered to be at high risk for OHSS. Repeat ovarian imaging is then obtained 4 to 5 days after initiating stimulation medications, once again on cycle day 9, and then daily along with daily measurement of estradiol levels once follicle diameters have reached 14 mm or the estradiol level exceeds 2,000 pg/ml. For patients who appear to develop high-risk signs, such as rapidly increasing estradiol levels or massive follicular recruitment, we may decrease medication dosages, alter the ratio of individual medications in the regimen, or stop medications altogether. Withholding medications at mid-cycle or delaying the administration of hcg is a maneuver sometimes referred to as coasting and has been shown to reduce the risk for OHSS in high-risk conditions (54). At this time, we do not assign arbitrary criteria for estradiol levels nor follicular number or size as automatically warranting such midcycle coasting measures; rather, these factors are all considered simultaneously along with the patient s clinical presentation and history. When conditions exist that are felt to warrant mid-cycle coasting, all stimulation medications are stopped and daily monitoring of follicle size and estradiol level is continued. Once estradiol levels plateau over the course of 2 to 3 days, we will either administer hcg and plan for oocyte retrieval in 36 hours or proceed straight to oocyte retrieval if we do not think it is safe to give hcg at all. Our experience has shown that allowing estradiol levels to decrease ultimately results in poor oocyte quality. We have also found that quick, drastic reductions in medications or coasting before follicular development of approximately 14 mm in diameter portends very poor oocyte retrieval results. In the rare but alarming case of OHSS morbidity that develops before the point where follicles have achieved a diameter of 14 mm, it is prudent to cancel the stimulation cycle altogether. This simply involves discontinuing all medications, including the GnRH agonist injections, after which the patient can either await an estrogen withdrawal menstrual flow to begin within 7 to 10 days, or take progesterone (either orally or by intramuscular injection) to induce a menstrual flow. Administration of hcg 36 hours before oocyte retrieval is instrumental in inducing final oocyte maturational changes, as well as for providing artificial luteal phase support for the endometrium. As mentioned in the Pathophysiology section, administration of hcg at the culmination of a COH cycle is, debatably, a key trigger for the development of OHSS. Despite general acceptance of this correlation, a multitude of studies can be found that support or refute the causative role of hcg in OHSS. When it is thought to be safe to administer hcg to a patient who in fact has high-risk factors (high-risk clinical profile, early signs or symptoms of OHSS, or a history of OHSS), we will give 5,000 IU instead of the more standard 10,000 IU to trigger ovulation or, in the case of IVF, the final stages of oocyte maturation. It should be recognized, however, that a minimal effective dose of hcg to induce oocyte maturation has yet to be conclusively established. If it is considered unsafe to give any hcg but follicles have developed beyond 14 mm in diameter, the physician must proceed to oocyte retrieval and plan on using other methods of luteal phase support. The embryology laboratory will need to be alerted that in vitro maturation of oocytes may be necessary. Proceeding to oocyte retrieval without the benefit of previous artificial maturation of oocytes will probably yield immature oocytes, which will require further maturation in vitro before fertilization is possible. Techniques for in vitro maturation and fertilization of immature oocytes have been reported (55). Progesterone supplementation after oocyte retrieval will be necessary for luteal phase support in the high-risk patient who has undergone GnRH agonist suppression and is not receiving hcg. Pituitary desensitization with GnRH agonist before a COH cycle will suppress endogenous LH secretion; such COH cycles will therefore inevitably have a luteal phase deficiency (56) that will require treatment to optimize conditions for implantation. In such circumstances, we will start progesterone supplementation on the second day after oocyte retrieval by giving either a single 100-mg intramuscular injection of progesterone in oil or a vaginal regimen of micronized progesterone. In the past, a GnRH agonist booster injection has been used to induce a gonadotropin surge for oocyte maturation/ luteal phase support when it was thought to be unsafe to give hcg at the culmination of a high risk cycle (57, 58). This maneuver would be useless, however, as an OHSS prevention measure in most COH cycles today, since most stimulation cycles are now preceded by GnRH receptor downregulation pituitary suppression. The concept of a GnRH booster method for oocyte maturation could have a resurgence however, if GnRH antagonists become commonplace for pituitary suppression in COH cycles. Much attention has been paid to whether the act of follicular puncture and aspiration has a role in preventing OHSS development in IVF cycles. It has been repeatedly documented that follicular aspiration cannot be relied on to prevent the development of OHSS or to prevent the worsening of an already existing case of OHSS (49, 59, 60). FERTILITY & STERILITY 887

6 Despite the documented inability to prevent OHSS, it remains commonplace for practitioners to attempt meticulous puncture and aspiration of all the stimulated follicles in the ovary at the time of oocyte retrieval. This is not without scientific reasoning. Surgical puncture of ovarian follicles has been reported to interfere with corpus luteum progesterone production. Garcia et al. (61) demonstrated that patients who underwent COH cycles and follicular aspiration with subsequent progesterone supplementation for luteal phase support had progesterone levels that were statistically similar to those seen in the luteal phase of control patients. Patients undergoing COH cycles and follicular aspiration without subsequent luteal phase support, however, had luteal phase progesterone levels that were significantly lower than those of controls. The study patients in this evaluation were previously assessed to have normal menstrual cycles without evidence of luteal phase deficiency. Of interest is one report in which ovarian cyst aspiration in patients with severe OHSS was shown to interrupt the progression of disease, resulting in immediate relief of OHSS symptoms (62). Use of this intervention as a therapy for severe disease, however, is apparently not commonplace, and any potential benefits should be weighed against the risks of subjecting the patient to a surgical procedure and causing ovarian hemorrhage. Presuming that OHSS relies at least in part on some mechanism of ovarian mediators, it is plausible that interruption of that mechanism may impede the process that is instrumental in the syndrome and thereby, hopefully, thwart any worsening of morbidity. A brief course of intravenous albumin is commonly used as an OHSS prevention technique at the time of oocyte retrieval. At The Johns Hopkins Hospital, this technique is implemented by infusing 200 cc of a 25% albumin solution (25 g of albumin per 100 cc of solution) intravenously over 4 hours; the regimen is initiated approximately 1 hour before retrieval begins. This protocol is reserved for patients who are felt to be at high risk for OHSS (high-risk clinical profile, current signs or symptoms of OHSS, or previous history of OHSS). The reasoning behind the use of intravenous albumin as OHSS prophylaxis is to increase intravascular oncotic pressure, thereby curtailing the exodus of free water from the intravascular space. We have not seen any complications or morbidity directly related to the use of albumin in any of our patients who have undergone this protocol. Albumin treatment as an OHSS preventive measure at the time of oocyte retrieval was first published by Asch et al. (63) and was subsequently shown by others to be a useful preventive technique (64, 65). Other investigators, however, have reported no effectiveness of intravenous albumin in preventing OHSS (66, 67). It should be appreciated that if OHSS signs or symptoms develop at the culmination of a COH cycle or after oocyte retrieval, an ensuing pregnancy may worsen the already present morbidity. This situation is attributed to the increase TABLE 2 Summary of OHSS prevention techniques. 1. Recognize the high-risk clinical profile for OHSS before starting a COH cycle or ovulation induction cycle: a young patient ( 30 years of age) with any of the widely recognized signs of PCOS. A history of immunologic hypersensitivity ( allergies ) has been implicated but remains to be conclusively ascertained as an independent risk factor for OHSS. 2. After GnRH agonist suppression, the patient with a high risk profile should start with the lowest standard gonadotropin dosing regimen; the dosing should thereafter be stepped up on the basis of estradiol response and follicular recruitment. 3. The patient who shows early indications of OHSS (subjective discomfort, massive follicular recruitment, a rapidly increasing serum estradiol level or one that is 5,000 pg/ml) during a stimulation cycle should have medication adjusted so that the estradiol level plateaus but does not decrease. If ominous signs of OHSS morbidity develop early in a cycle (before follicles reach 14 mm in diameter), serious consideration should be given to stopping all medication and cancelling the cycle. 4. If signs or symptoms of grade 1 OHSS are evident toward the culmination of a COH cycle, especially if conditions have occurred that warrant coasting measures, consideration should be given to administering a lower-than-standard dose of hcg for oocyte maturation and luteal phase support (e.g., 5,000 IU instead of 10,000 IU). If grade 2 OHSS morbidity is already present at the culmination of a COH cycle, consideration should be given to withholding hcg altogether and proceeding straight to follicular aspiration and oocyte retrieval and giving progesterone for luteal phase support. In vitro oocyte maturation will be necessary if hcg is not given. 5. Use a prophylactic regimen of intravenous human albumin at the time of oocyte retrieval if the patient has a clinical profile indicating OHSS, if any signs or symptoms of OHSS occurred during the cycle, or if the patient has a previous history of OHSS. The actual preventive nature of this intervention is debatable. 6. Consider cryopreserving all embryos resulting from a COH/IVF cycle if OHSS morbidity is evident at the time when embryo transfer would have otherwise taken place. Embryo transfer can be postponed to the luteal phase of a subsequent cycle, when OHSS has completely resolved. Note: COH controlled ovarian hyperstimulation; OHSS ovarian hyperstimulation syndrome; PCOS polycystic ovary syndrome. Whelan. Ovarian hyperstimulation syndrome. Fertil Steril in endogenous hcg that arises from trophoblast, thereby supporting the theory that hcg plays an integral role in the mechanism of OHSS. Consideration should therefore be given to cryopreservation of all embryos resulting from this cycle, deferring embryo transfer to a subsequent cycle after OHSS has completely resolved. This approach has been shown to be an effective preventive measure against OHSS and may also result in a higher pregnancy rate (per cycle) compared with transferring the embryos to the uterus in the cycle complicated by OHSS (68, 69). To take advantage of this preventive intervention, an ovulation induction cycle may need to be converted to an IVF cycle if evidence of OHSS becomes apparent prior to intrauterine insemination (IUI) or timed coitus (Table 2). 888 Whelan and Vlahos The ovarian hyperstimulation syndrome Vol. 73, No. 5, May 2000

7 MANAGEMENT Although the precise pathogenesis of OHSS has yet to be determined, it is, fortunately, a time-limited phenomenon. As long as morbidity is attended to appropriately and promptly, the patient can expect a full recovery within 10 to 14 days from the onset of initial symptoms. As previously mentioned, clinical resolution seems to parallel the decline of the serum hcg remaining after the triggering dose of hcg. Correspondingly, the clinician should realize that if a patient was inseminated or had an embryo transfer before developing OHSS, an ensuing pregnancy could prolong the typical time frame and cause an otherwise improving scenario to reverse course and rapidly become worse. When signs and symptoms of OHSS develop, the clinician must first decide between hospital admission and outpatient management. It is commonly accepted and appropriate to assume that a large percentage of all patients undergoing ovarian hyperstimulation protocols may develop some symptoms of grade 1 OHSS (as described by the classification system of Golan et al. [3]). The patient complaining simply of abdominal bloating or mild discomfort that is not accompanied by vomiting or diarrhea or other signs of more advanced disease can be reassured that the symptoms should be time limited, instructed to avoid impact-type exercises or physical exertion, and warned about symptoms of progressing disease. When a patient begins to describe her discomfort as pain, or if she has nausea that diminishes her appetite, or if she vomits or has diarrhea, grade 2 OHSS is diagnosed. As previously mentioned, the measurement of ovarian dimensions as described in the Golan classification of grade 2 is no longer thought to be clinically useful. The onset of vomiting or diarrhea, particularly if developing within 48 hours of receiving hcg, is significantly ominous for the potential of severe disease. All patients with evidence of grade 2 or 3 OHSS must have a complete physical and pelvic examination, blood tests for measurement of sodium, potassium, creatinine and hematocrit, and abdominal ultrasonography to determine the presence of ascites. These parameters are then used to help decide whether hospitalization or outpatient management is most appropriate for the patient with grade 2 or 3 disease. Hospital admission criteria in grade 2 or 3 are as follows: 1. Patient history or symptoms a. Nausea or abdominal pain that causes intolerance of food or liquid b. Vomiting or diarrhea within 48 hours of hcg injection 2. Physical examination signs a. Hypotensive blood pressure relative to the patient s baseline pressure or any other clinical signs or symptoms of hypotension b. Decreased breath sounds over any of the lung fields (a positive finding indicates grade 4 disease) c. Tense, distended abdomen or any other signs of ascites d. Peritoneal signs (e.g., rebound pain after percussion, costovertebral angle tenderness, or heel tap pain in abdomen); positive findings indicate grade 4 disease 3. Blood tests (abnormal findings indicate possible grade 5 disease) a. Hematocrit 48% b. Sodium level 135 meq/l c. Potassium level 5.0 meq/l d. Creatinine level 1.2 mg/dl 4. Abdominal ultrasound findings: presence of fluid pockets between loops of bowel when patient is lying supine. Note that while ultrasonographic evidence of ascites can be an appropriate independent indication for admission, it is difficult to describe discrete levels of objectivity for this variable. For instance, if small pockets of fluid are noted between bowel loops but the patient has a benign physical examination, admission may not be necessary. Instead, one may choose daily outpatient monitoring. If, however, large pockets of fluid are noted with floating loops of bowel, admission to the hospital would be indicated, even if the patient is tolerating the condition well. For grades 2 or 3 disease, hospitalization is optional and dependent on the physician s clinical judgment. The parameters listed here for hospital admission criteria have been useful at our institution and are presented only as a suggested protocol for management. We consider severe OHSS (i.e., Golan grade 4 and 5 disease) to be potentially life-threatening, therefore warranting hospitalization in all cases. The detailed aspects of outpatient and hospitalized managements are discussed in the next section. Outpatient Management Patients with grade 2 or 3 disease should maintain a schedule of only light physical activity. Hyperstimulated ovaries are markedly enlarged. This condition is a risk factor for ovarian torsion, and this risk may be minimized if the patient avoids strenuous activity (e.g., aerobic exercise). Most patients will feel too uncomfortable to engage in such activity. Ovarian torsion or hemorrhagic rupture of cysts is possible, however, even in a resting patient, and the physician should have a low threshold of suspicion for these potential complications in all hyperstimulated patients. Strict bed rest, on the other hand, is unwarranted in the outpatient management of OHSS. These patients are relatively hyperestrogenic and may be volume-depleted from low appetite conditions that may predispose them to thromboembolic events. A prolonged sedentary position would only serve to increase the risk for this complication. Prostaglandin inhibitors have been studied as treatment for OHSS. Borenstein et al. (70) demonstrated that for patients with severe OHSS, paracentesis alone was superior to FERTILITY & STERILITY 889

8 a medical regimen that included indomethacin in bringing about resolution of the disease. Contradictory results have been found in the OHSS rabbit model. Schenker et al. (21) demonstrated that indomethacin can prevent induced OHSS. Later, however, Pride et al. (71) suggested that prostaglandin F may be instrumental in preventing severe manifestation of induced OHSS when the rabbit model was treated with a histamine-1 receptor blocker. Although some protocols have advocated abundant oral fluid intake for the patient with mild or moderate disease (4, 72), patients should not feel that they need to force a diuresis but should be drinking at least 1Loffluid per day. Patients should record the volume of their 24-hour fluid intake and urine output. These volumes are reviewed with the patient on a daily basis, usually over the phone. Fluid intake of 1,000 ml/d, urine output of 1,000 ml/d, or a fluid balance discrepancy of 1,000 ml/d, are matters of concern. Many popular sports drinks are electrolyte balanced to correct for dehydration conditions. These would seem to be optimal in the outpatient management of OHSS patients who require hydration but must minimize free water, which will probably contribute to third-space fluid and ascites. Weight changes should also be monitored daily, and patients should be queried about symptoms and appetite. If symptoms are worsening, appetite is decreasing, or weight continues to increase at 2 lb/d or more, the patient should be brought back to the office for repeated physical examination, blood tests, and abdominal ultrasonography. On the basis of this evaluation, it should be redetermined whether outpatient management is still appropriate. As a reminder, in the context of OHSS management, if a patient has met the criteria for any stage of OHSS in the course of a stimulation cycle, consideration should be given to the possibility of canceling the stimulation cycle if it is early in the cycle or withholding hcg injection if the cycle is at culmination. If hcg has already been administered, the patient and her partner need to be counseled about the potential risks of proceeding with IUI or embryo transfer. The patient should be aware that her condition may worsen if pregnancy ensues (Table 3). Hospitalization Management Once a patient meets any of our aforementioned hospitalization criteria for grade 2 or 3 OHSS or has any indications of grade 4 or 5 disease, admission to the hospital is warranted. In addition to daily physical examination, checking of vital signs every 4 hours, and tabulation of fluid balance every 4 hours, the following parameters are monitored on a daily basis: Leukocyte count Hemoglobin concentration and hematocrit Full electrolyte panel Liver function tests Measurement of daily weight and abdominal girth TABLE 3 Summary of outpatient OHSS management. Grade 1 Offer reassurance, tell patient to avoid strenuous exercise or exertion. The patient may use acetaminophen as needed for relief from pelvic discomfort. Counsel about symptoms of worsening disease. Grade 2 Perform physical examination, measure serum electrolytes and hematocrit, and obtain abdominal ultrasound to assess for ascites. Make decision about hospitalization versus outpatient management (see notes regarding hospitalization criteria for OHSS grade II/III). Instruct the patient to keep physical activity to a minimum, drink at least 1,000 ml of fluid per day, and tabulate total fluid intake and urine output at 24-hour intervals. The patient should contact the office daily to report input and output tabulations, weight changes, and assessment of symptoms. Worsening symptoms or quickly progressing increases in weight ( 2 lb/d) should warrant a prompt return to the office for repeated physical examination, blood tests, and abdominal ultrasonography and reassessment of the possible need for hospitalization. Grade 3 Use same protocol as that for grade 2 management (see notes about relative interpretations of abdominal ascites as diagnosed by ultrasonography). Note: Based on the classification system of Golan and colleagues (3). OHSS ovarian hyperstimulation syndrome. Whelan. Ovarian hyperstimulation syndrome. Fertil Steril Prothrombin time (PT) and partial prothrombin time (PPT) are initially measured to obtain a baseline value in case therapeutic anticoagulation is later necessary. It is commonly acknowledged that these two measurements are essentially useless in predicting thrombotic events and therefore, unless the patient suffers from a known coagulopathy, it is not necessary to repeat coagulation profiles on a daily basis. Likewise, if liver function tests are initially normal, these only need to be repeated periodically if the patient s hospital stay becomes prolonged. A chest x-ray and pulse oximetry are mandatory for any patient with shortness of breath or any other signs of pulmonary compromise, but these studies should not be routine for every patient initially admitted to the hospital with OHSS. Repeated abdominal ultrasonography should be reserved for situations in which the findings may direct clinical management or as needed for paracentesis. Leukocyte count, hemoglobin level, and hematocrit should be measured on at least a daily basis, since the degree of hemoconcentration and blood viscosity have been shown to closely correlate with the severity of OHSS (70). It is not uncommon for OHSS patients to have a leukocyte count in the range of 20,000 30,000 cells/mm 3. The patient s overall stress response to her discomfort, as well as hemoconcentration, accounts for this finding. Although leukocytosis is 890 Whelan and Vlahos The ovarian hyperstimulation syndrome Vol. 73, No. 5, May 2000

9 commonly found, the condition should not be regarded lightly but should rather serve as a daily reminder of the propensity toward thrombotic events. As previously noted, a leukocyte count of 22,000 cells/mm 3 has been reported as an ominous sign of imminent thromboembolism (33). Daily assessment of electrolytes is necessary since the hyperpermeability of the vasculature in OHSS can result in rapid dynamic changes of both sodium and potassium levels. Information should also be available on a daily basis to be used for calculation of creatinine clearance. We have found daily weight and abdominal girth measurements to be indirect but reliable indices of ascite accumulation. Weight loss and reversal of abdominal girth seem to correlate well with reversal of OHSS. With the above parameters serving as a framework for daily clinical assessment, a tripartite management plan is instituted while the patient is hospitalized: fluid management, prevention of thrombosis, and treatment of ascites. Fluid Management Typically, the patient admitted for severe OHSS will initially be hypovolemic from decreased oral intake, thirdspace fluid retention, and vomiting or diarrhea. All of our patients are initially treated with 1Lofnormal saline intravenously over 1 hour. Lactated Ringer solution is not recommended, since OHSS patients have a propensity to be hyponatremic. If the patient has an appreciable urine output in response to the fluid bolus (preferably at least 50 ml over the hour after the fluid bolus), an IV fluid maintenance protocol is initiated. Specifically, 5% dextrose in normal saline (D5NS) is infused at ml/h, urine output is assessed every 4 hours, and hematocrit is determined approximately 4 hours after the start of IV hydration to ensure that hemoconcentration is reversing. Admittedly, intravenous fluid hydration to correct hemoconcentration will contribute to ascites development while the patient is in a hyperpermeable state. As long as pulmonary status is closely monitored, even moderate ascites is probably less likely to precipitate an acute emergency compared with severe hypotension, which can quickly become a critical complication. If there is inadequate response in urine output from the initial 1-L fluid bolus, IV crystalloid fluids are stopped and a regimen of low-volume, hyperosmolar IV therapy is begun. An IV infusion of 200 ml of 25% albumin solution is given over 4 hours (i.e., total IV input of 50 ml/h times 4 hours for a total of 50 g of albumin per 4-hour interval), with a recheck of hematocrit approximately 1 hour after the infusion. This protocol is repeated in a serial fashion until the hematocrit is brought within 36% 38%. The relatively low total IV input of a hyperosmotic agent at this point should help to increase intravascular oncotic pressure in order to draw third-space fluid back into the intravascular space. Once a hematocrit of 36% 38% has been achieved, furosemide (20 mg IV) may be given to assess renal response. It is important to infuse intravenous albumin slowly, since a bolus may reverse hemoconcentration so quickly that hemodilution actually develops, with subsequent leakage of free water back into third spaces (e.g., pulmonary edema) before renal filtration occurs. It is also important to document a relative improvement in hemoconcentration before diuretics are initiated. Overzealous use of diuretics before normalizing intravascular volume will only worsen hemoconcentration, increase the risk for a thrombotic event, and cause hypotensive sequelae. Human albumin for hospital use in the United States has been subjected to alcohol fractionation and heat inactivation so that it is free of both enveloped and nonenveloped viruses. Other plasma expanders have been used to increase intravascular oncotic pressure and thus bring third-space fluid back into the intravascular space, including mannitol (4), dextran (73), and fresh frozen plasma (70). In these studies, dextran was associated with development of ARDS, and neither mannitol nor fresh frozen plasma were shown to be superior to albumin in treating OHSS. Intravenous albumin administered to the OHSS patient as a single therapeutic agent has been shown to normalize hematocrit and induce diuresis (37). In our experience, it is not unusual for several days to elapse during which IV crystalloid therapy, albumin therapy, and medical diuresis need to be titrated at 4- to 8-hour intervals to achieve and maintain euvolemia in the patient with severe OHSS. In the early phase of hospitalization, patients are not necessarily kept fasting. They are usually too nauseated to eat or drink anything. Under these circumstances, the patient may be allowed to have sips of clear liquids as tolerated. As the patient becomes euvolemic with spontaneous urine output, she will usually have a corresponding increase in appetite. It is at this juncture in the natural course of the syndrome that third-space fluid begins to spontaneously reenter the intravascular space, hemoconcentration begins to reverse, and natural diuresis soon follows. At this point, a fluid conservation regimen is begun IV crystalloid input is kept at a minimum rate (50 ml/h) or IV fluids are stopped altogether, and the patient is allowed to drink clear fluids but is restricted to a maximum total input of 1 L/d. We believe that fluid restriction in the resolution phase of the syndrome will prevent hemodilution and thus not impede the shift of ascitic fluid and third-space fluid back into the intravascular space. Once the patient has reached this stage, she is considered ready to be discharged from the hospital as long as she has adequate spontaneous urine output, a relatively benign physical examination, and a good appetite. The patient is then switched to an outpatient management protocol until all signs and symptoms of OHSS have resolved. If subsequent pregnancy testing is positive, outpatient monitoring is con- FERTILITY & STERILITY 891