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Ovarian hyperstimulation syndrome: strategies for prevention
RBMOnline - Vol 7. No 1. 43–49 Reproductive BioMedicine Online; www.rbmonline.com/Article/839 on web 28 March 2003
Article Ovarian hyperstimulation syndrome: strategies for prevention Zev Rosenwaks, MD, is Director of The Center for Reproductive Medicine and Infertility, world-renowned infertility clinic at New York Weill Cornell. He is Professor of Obstetrics and Gynecology at Weill Medical College of Cornell University and was appointed the Revlon Distinguished Professor of Reproductive Medicine in Obstetrics and Gynecology in 1994. Dr Rosenwaks is a diplomate of the American Board of Obstetrics and Gynecology and received his subspecialty certification in Reproductive Endocrinology in 1981. He is a noted world authority on reproductive endocrinology and infertility and one of the founding pioneers in the assisted reproductive technologies. He has authored over 300 scientific papers, 45 book chapters and five textbooks. Dr Zev Rosenwaks Dehan Chen, Lynn Burmeister, Dan Goldschlag, Zev Rosenwaks1 The Center for Reproductive Medicine and Infertility, Weill Cornell Medical College, 505 East 70th Street, HMT-340, New York, NY 10021, USA 1Correspondence: e-mail: [email protected]
Abstract Ovarian hyperstimulation syndrome (OHSS) is a serious, iatrogenic complication of ovarian stimulation. The following report is a review of traditional and new strategies to prevent the development of OHSS. Techniques such as reducing the ovarian stimulus, coasting and cryopreservation are discussed. Other more investigative strategies are also summarized, including follicular aspiration, in-vitro maturation of immature oocytes, the use of gonadotrophin-releasing hormone (GnRH) agonists to trigger ovulation and the use of volume expanders such as hydroxyethyl starch. In addition, a review of the internal experience with OHSS at the authors’ institution is described. All these preventative approaches are based on current understanding of the physiologic mechanisms involved in the pathogenesis of OHSS.
Keywords: coasting, cryopreservation, IVF, OHSS, ovarian hyperstimulation
Introduction Ovarian hyperstimulation syndrome (OHSS) is a serious and potentially life-threatening complication of ovarian stimulation. Typically, the syndrome is seen in women who undergo ovulation induction with exogenous gonadotrophins, but it can also be seen rarely after administration of clomiphene citrate. The incidence of OHSS has been reported to be as high as 33%, with severe OHSS occurring in 0.5–4% of patients (Navot et al., 1992; Beerendonk et al., 1998; Enskog et al., 1999; Whelan and Vlahos, 2000). Although the incidence of severe OHSS is relatively low, it can result in significant morbidity and, rarely, even death. Generally, OHSS is preceded by multiple follicular development combined with a high serum oestradiol concentration. Luteinization is essential for its development. The early form occurs 3–7 days after human chorionic gonadotrophin (HCG) administration, while the late form of OHSS occurs 12–17 days after HCG administration. As clinical resolution usually parallels the decrease in residual concentrations of exogenous HCG, successful pregnancy with subsequent increase in endogenous HCG may account for the late form of OHSS. It is unclear whether women who present
with the so-called late forms also exhibit subclinical manifestation earlier in the luteal phase. Multiple pregnancy is also a risk factor for the late form of OHSS (Beerendonk et al., 1998). Ovarian enlargement and increased capillary permeability leading to a ‘third-space’ fluid shift characterize OHSS. These changes may cause haemoconcentration, electrolyte disturbances, liver and kidney dysfunction and thromboembolic sequelae. Physical symptoms primarily consist of distended abdomen, gastrointestinal discomfort, dyspnoea and decreased urine output. Clinical signs may include the following: rapid weight gain, oliguria, haemoconcentration, leukocytosis, hypovolaemia, electrolyte imbalance, ascites, pleural and pericardial effusion, adult respiratory distress syndrome, hypercoagulability and multiple organ failure. Death is rarely reported in the literature (Whelan and Vlahos, 2000). Treatment consists of supportive care and maintenance of vascular space integrity. Clinical signs and symptoms such as weight gain, changes in abdominal girth and haemoconcentration are useful to monitor clinical progression. Severe OHSS often requires hospitalization and medical
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intervention. Intravenous fluid (normal saline) and plasma expanders, such as albumin, may be useful in maintaining intravascular volume, and anticoagulation may be necessary to prevent thrombosis. Periodic paracentesis and rarely pleurocentesis may be employed to relieve physical discomfort, as well as to alleviate renal and respiratory compromise. Fortunately, OHSS is self-limiting and if pregnancy does not occur, recovery often begins at the end of the luteal phase. However, if pregnancy occurs, the time course of the disease may be as long as several weeks, presumably until the luteotrophic drive by endogenous HCG diminishes at 7–10 weeks gestation (Grudzinskas and Egbase, 1998).
Pathophysiology Morbidity in OHSS is primarily associated with a shift of intravascular fluid to the third space. This shift is believed to occur secondary to an elevation of factors that increase vascular permeability, which presumably rise as a consequence of exposure to the ovulatory stimulus. It is of relevance to note that exposure to HCG is most often responsible (or even obligatory) for the development of OHSS. Moreover, it has been observed that the LH surge elicits an inflammatory reaction, resulting in follicular wall breakdown and oocyte release, the intermediates of which have been implicated in the aetiology of OHSS. Thus, it should come as no surprise that increased concentrations of inflammatory cytokines such as interleukin (IL)-1, IL-2 and IL-6, along with an increase in vascular endothelial growth factor (VEGF), are associated with severe forms of this syndrome. Indeed, infusion of IL-2 into healthy subjects leads to the ‘vascular leak syndrome’, with the rapid accumulation of extravascular fluid resulting in ascites and pulmonary oedema (Oppenheim et al., 1991). HCG production has been shown to stimulate IL-2 from granulosa cells, and patients who develop severe OHSS have higher IL-2 concentrations in follicular fluid and serum compared with those who do not develop this syndrome, despite similar oestradiol concentrations and number of follicles (Orvieto et al., 1995). Additional evidence that these factors may be responsible for the syndrome comes from the observation that VEGF mRNA is highly correlated to HCG exposure in a dose- and time-dependant manner (Neulan et al., 1995). VEGF is known to increase endothelial cell permeability. VEGF mRNA is expressed in luteinized granulosa cells and has also been shown to be associated with OHSS. Moreover, infusion of anti-serum to VEGF leads to a 70% reduction in capillary leakage (McClure et al., 1994). The ovarian renin–angiotensin system has also been implicated as a putative mediator for OHSS development. Indeed, high renin concentrations are correlated with the severity of OHSS. Further studies may elucidate the specific roles of cytokines (IL-1, IL-6, IL-8, tumour necrosis factor (TNF) α), histamine, and prostaglandins in the pathophysiology of OHSS (Golan et al., 1989; Orvieto and Ben-Rafael, 1998).
Risk factors
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Prevention of OHSS relies principally on identifying patients at risk and individualization of stimulation protocols. Risk factors predisposing to OHSS include polycystic ovarian disease (PCOD), young age, history of previous OHSS and
low body weight. Patterns and response to ovarian stimulation may also provide clues as to susceptibility to OHSS. For example, the development of a large cohort of antral follicles associated with high and rapidly increasing oestradiol concentrations >3000 pg/ml on day of HCG, more than 20 follicles seen on ultrasound in the late follicular phase and greater than 15 oocytes retrieved, are all potential risk factors (Morris et al., 1995; Enskog et al., 1999; Reljic et al., 1999).
Prevention strategies Ovarian stimulation Women with exaggerated responses to gonadotrophins and particularly women with PCOD represent the greatest challenge. It is necessary to establish each individual’s FSH threshold dose, since exceeding this threshold may lead to excessive multifollicular development, thus increasing the risk for OHSS. It is therefore useful, in this highly susceptible group, to begin stimulation with relatively lower gonadotrophin doses, and then carefully titrate. Often this subgroup benefits from dual suppression with oral contraceptives and GnRH agonists, along with relatively low gonadotrophin doses (Damario et al., 1997). Careful monitoring of serum oestradiol concentrations with ultrasonographic assessment of follicle size and number helps to identify patients at risk. When possible, after establishing a given gonadotrophin threshold and achieving critical oestradiol concentrations (~200–300 pg/ml) and several follicles of 11–12 mm size, an attempt should be to step down gonadotrophin dosages. This approach allows the ≥12 mm follicles to continue to develop in a relatively low FSH milieu while theoretically ‘starving’ the smaller follicles. The net impact of such an approach results in fewer intermediate and small follicles on HCG day, thus theoretically reducing the risk of OHSS. Furthermore, as HCG is a risk factor for OHSS, it seems prudent to reduce the magnitude of this stimulus when possible. This can be accomplished by withholding or reducing the ovulatory dose of HCG. The customary dose of HCG is 10,000 IU; however, some authors advocate reducing the dose of HCG to trigger ovulation (Abdalla et al., 1997). We also employ this method to help reduce the incidence of OHSS; women with oestradiol concentrations exceeding 2000 pg/ml receive between 3300 and 5000 IU of HCG. Lowering the dose of HCG does not appear to affect oocyte quality or pregnancy rates. The administration of HCG is withheld or delayed when oestradiol concentrations exceed 3000 pg/ml.
Coasting Coasting refers to withholding gonadotrophins in individuals who exhibit extremely high oestradiol concentrations (>3000 pg/ml) and delaying HCG administration until oestradiol concentrations decrease, usually to concentrations between 2000 and 2500 pg/ml. This is an attractive alternative to cycle cancellation and appears to reduce the risk of OHSS. This approach may reduce the number of intermediate and small follicles by virtue of removing the FSH stimulus required to maintain their continued growth. The net reduction of small and intermediate follicles presumably reduces the overall
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release of potential OHSS inducing intermediates following HCG administration, thus reducing OHSS risk without reducing pregnancy success. The risk of coasting includes a reduction in the number of mature oocytes retrieved and a reduction in oocyte quality (Urman et al., 1992; Dhont et al., 1998; Tortoriello et al., 1998; Fluker et al., 1999). Retrieval should be cancelled if oestradiol concentrations drop by more than 20% after HCG administration, as oocyte quality and pregnancy rates are generally poor when such a pattern is observed (Benadiva et al., 1997).
Cryopreservation Oocyte retrieval and cryopreservation of all ensuing embryos is another alternative to cycle cancellation, since pregnancy and rising endogenous HCG titres exacerbate the risk for developing OHSS. This concept was confirmed by Morris et al. (1995), who noted that oocyte donors, who themselves did not become pregnant, had a very low risk for developing OHSS despite high oestradiol concentrations (>4000 pg/ml) after ovarian stimulation. Thus, for individuals who are at high risk for developing OHSS (i.e. oestradiol >3000 pg/ml and ≥20 oocytes retrieved), consideration could be given to avoiding fresh transfer in the cycle of retrieval with cryopreservation of all embryos (Egbase, 2000). If OHSS is felt to be imminent at the time of retrieval or shortly thereafter, embryos can be frozen at the pronuclear stage. The decision as to whether to cryopreserve all embryos can also be made based on clinical progression while waiting for day 5 (blastocyst) transfer. Fresh transfer should occur if no obvious signs or symptoms of OHSS are observed. Another strategy is to freeze a cohort of pronuclear embryos while allowing the rest of the embryos to progress to the blastocyst stage. Such decisions are usually based on an individual institution’s experience and success rates with pronuclear freezing, blastocyst culture, and blastocyst freezing. There have been several reports confirming that subsequent cryopreserved–thawed embryo transfers in such cycles yield reasonable pregnancy rates (Pattinson et al., 1994; Tiitinen et al., 1995; Queenan et al., 1997; Feraretti et al., 1999).
Intravenous albumin administration Several investigators have proposed that the prophylactic use of albumin, administered during and or after oocyte retrieval, may diminish the incidence of OHSS. This is accomplished presumably by maintaining intravascular oncotic pressure and decreasing third space fluid loss. It has also been postulated that albumin may bind putative intermediates which increase capillary permeability (Navot et al., 1992). Chen et al. (1997) concluded that intravenous administration of albumin after oocyte retrieval may prevent the development of severe OHSS in patients who either did not conceive or who had singleton pregnancies. However, they did not show that the use of albumin decreased the risk of OHSS in patients with highorder pregnancies. Alboulghar et al. (2000), in a meta-analysis of three randomized studies, concluded that IV albumin administration helps to reduce the incidence of severe OHSS. However, other investigators have not been able to confirm its efficacy (Ndukwe et al., 1997; Ben-Chetrit et al., 2001). Additional multicentre randomized controlled trials with larger numbers are still needed to determine if IV albumin can actually prevent severe OHSS in high-risk patients.
Intravenous hydroxyethyl starch administration Hydroxyethyl starch (HES) is a plasma expander that has gained recent attention as an alternative to albumin in reducing the incidence of OHSS. Because HES is a non-biological substance, it avoids any potential concern about viral transmission that is present with albumin. Two prospective randomized controlled studies demonstrated the superiority of 6% HES in preventing the development of OHSS versus placebo (Konig et al., 1998; Gokmen et al., 2001). Gokmen et al. also concluded that HES was as effective as albumin in the prevention of OHSS. One report even suggested that HES was superior to human albumin in the treatment of severe OHSS in terms of duration of hospitalization, urine output and incidence of paracenteses (Abramov et al., 2001). However, these results were contradicted in another study (Gamzu et al., 2002). While HES is considered to be well tolerated, one case report illustrated the dangers of over-infusion of HES (Kissler et al., 2001). In this case report, a patient was given large amounts of HES for 10 days to treat her severe OHSS. Well after her apparent recovery, the patient developed a pleural effusion and altered blood coagulation parameters. Analysis of the pleural effusion revealed a high concentration of HES leading to speculation that the loss of HES into the third space actually prolonged and aggravated the clinical course of OHSS.
Gonadotrophin-releasing hormone (GnRH) agonists/antagonists Typically, HCG is used as the surrogate to LH for oocyte maturation and ovulation induction in women undergoing ovarian stimulation. Given its longer half-life (>24 h versus 60 min for LH), HCG administration results in a prolonged luteotrophic effect (Fauser et al., 2002). This sustained effect may further exacerbate the risk for developing OHSS. An alternative to HCG-induced ovulation is the use of GnRH agonists. GnRH agonists can induce a sustained (>24 h) release of LH (and FSH) from the pituitary that can effectively induce oocyte maturation and ovulation (Lewit et al., 1996). However, the major limitation to its use is that GnRH agonists are ineffective in women who have a low endogenous gonadotrophin reserve or when suppressed by pituitary downregulation with GnRH agonists. Itskovitz-Eldor et al. (2000) overcame this problem by using GnRH antagonists to suppress ovulation during stimulation and showed that ovulation could then be effectively triggered with GnRH agonist. They concluded that the use of GnRH agonist to trigger ovulation is an effective way of stimulating ovulation in the high-responder whilst potentially reducing the risk of OHSS. Furthermore, GnRH antagonists can also be used to alleviate the development of OHSS in patients at high risk by blocking endogenous stimulation of the ovary (de Jong et al., 1998). Other authors have also concluded that the use of GnRH antagonists to suppress ovulation is associated with a lower risk of developing OHSS when compared with GnRH agonist cycles (Ludwig et al., 2000). Further trials are needed to confirm these observations.
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Recombinant human LH Recombinant human LH (rhLH) is also a viable alternative to HCG as an ovulatory stimulus. In fact, rhLH may prove to be more ‘physiological’ than HCG, given the shorter half-life of rhLH versus HCG (1–5 h for rhLH versus >1 day for HCG). As prolonged stimulation of the corpora lutea is believed to be a key factor in the development of OHSS, the shorter effect of rhLH should be useful in avoiding OHSS. The European Recombinant LH Study Group found that a single dose of rhLH resulted in a highly significant reduction in OHSS compared with HCG (European Recombinant LH Study Group, 2001). At this time, however, rhLH is not yet widely available in the United States.
Follicular aspiration It has been suggested that follicular aspiration could potentially reduce the risk of OHSS. Surgically induced intrafollicular haemorrhage has a negative impact on the corpus luteum. In essence, the intraovarian mechanisms responsible for OHSS may be modified by surgical follicular aspiration and hence meticulous aspiration of all follicles should be performed (Navot, 1992). Follicular aspiration for IVF may remove the source of cytokines as well as VEGF and other factors implicated in the development of OHSS, thus reducing the risk of serious sequelae. Some investigators have performed early unilateral cyst aspiration in the attempt to avoid the development of OHSS; however, reports from these studies are conflicting (Tomazevic and Vrtovec, 1996; Egbase et al., 1997, 1999). To date, there has only been one report in which ovarian cyst aspiration in patients with severe OHSS was shown to decrease the progression of OHSS (Fakih and Bello, 1992).
In-vitro maturation of immature oocytes It has been proposed that, for women who are at high risk of OHSS, i.e. those with polycystic ovarian disease, avoiding or minimizing ovarian stimulation may be the most reasonable approach to avoid OHSS. This approach requires in-vitro maturation of immature oocytes (IVM) retrieved from nonstimulated or minimally stimulated ovaries. Child et al. (2001) and Cha and Chian (1998) have demonstrated that reasonable pregnancy rates can be achieved in these individuals following IVM. It should be emphasized, however, that IVM protocols have not achieved pregnancy rates that are comparable to rates following ovarian stimulation and IVF of mature oocytes.
Table 1. Incidence of OHSS. New York Presbyterian–Weill Cornell Medical Centre July 1997–December 2000. Number Cycles Retrievals OHSS (mild and moderate)a Severe OHSSb
aIncludes any patient that presented for evaluation of mild abdominal discomfort <7 days post-HCG. bThree severe OHSS patients hospitalized.
ovarian stimulation. The incidence of OHSS excluding patients with early onset complaints was 0.4%. There were only three cases of severe OHSS requiring hospitalization during this time period (0.00055% of cycles), and only one of these cases required paracentesis. The other two cases resolved spontaneously. In all three cases the patients were pregnant, and each of the patients went on to deliver children (two singletons, one set of twins). This retrospective review represents the largest data set analysed for OHSS incidence in IVF from one institution in the literature. The overall rate of OHSS at Cornell of 1.0% using the most liberal criteria for OHSS is on the low end of the reported incidence of 1–10% of IVF cycles (Forman et al., 1990; Wada et al., 1990; MacDougall et al., 1992). Similarly, the incidence of severe OHSS of 0.00055% at Cornell compared favourably with the reported incidence of 0.5–2% of IVF cycles (Forman et al., 1990; SART, 1992). Clearly, much of the reduction in OHSS can be attributed to an improved understanding and awareness of the risk factors involved with OHSS that has evolved over time. Outcomes after coasting or cryopreservation were also compared in patients at risk of developing OHSS over a 5-year period at Cornell. Patients were coasted when their serum oestradiol concentration was ≥3000 pg/ml, or when their ultrasound revealed numerous immature follicles (<16 mm in diameter) in conjunction with a rapidly increasing serum oestradiol concentration. Administration of HCG was withheld until the serum oestradiol concentration dropped below 3000 pg/ml. Oocyte retrieval was cancelled if the oestradiol concentration dropped ≥20% after HCG administration. Figure 1 is a
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Table 1 summarizes the incidence of OHSS during a 3.5-year period. Although 54 patients complained of symptoms (1% of cycles), most of the cases involved symptoms of mild abdominal discomfort that occurred less than 7 days after HCG administration, and resolved without further sequelae. Some argue that these early, mild cases do not represent true OHSS, but are part of the spectrum of anticipated symptoms from
Oestradiol (pg/ml)
The Cornell experience The total experience and incidence of OHSS following IVF at Cornell from July 1997 through December 2000 has been reviewed. Particular attention was given to the common OHSS prevention strategies and their impact on pregnancy outcome.
5409 4443 22 3
4500 4000 3500 3000
Cancelled Coast and transfer
2500 2000 1500 1000 500 0 Peak
On day of HCG
Post HCG
Figure 1. Oestradiol concentrations (pg/ml): cancelled coast cycles versus coast and transfer. Thirty-six coasted patients cancelled due to drop in oestradiol, two patients cancelled due to high oestradiol, five patients cancelled for other reasons.
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Table 2. Coasting interval.
No. retrievals/cycles (% cancelled) Peak oestradiol (pg/ml)a Oestradiol on HCG day (pg/ml)a Mature oocytes (n)a Embryos transferred (n)a Miscarriage rate (%) Deliveries/cycle (%) No. deliveries/transfer (%)
Number of days coasted 1 2
3
4
>4
35/42 (17)
34/48 (29)
13/22 (41)
7/12 (42)
0/8 (100)
3227 ± 800 2539 ± 736
3903 ± 610 2247 ± 702
4364 ± 778 1977 ± 633
4892 ± 904 1852 ± 725
5258 ± 1035 –
13.5 ± 4.8 3.7 ± 1.5 2/26 (8) 24/42 (57) 24/35 (69)
11.7 ± 5.2 2.8 ± 1.6 9/26 (35) 17/48 (35) 17/34 (50)
11.6 ± 6.9 2.0 ± 1.7 1/7 (14) 6/22 (27) 6/13 (46)
10.9 ± 6.4 2.7 ± 1.8 0/5 (0) 5/12 (42) 5/7 (71)
– – – – –
aMean ± SD.
Table 3. Coasting (CO) versus cryopreservation (CR). New York Presbyterian–Weill Cornell Medical Centre 1995–1999.
Cycles (n) Retrievals (n) Transfers (n) Cancellation rate (%) Peak oestradiol (pg/ml)a Oestradiol on HCG day (pg/ml)a Mature oocytesa Embryos transferreda Early onset symptoms (%) OHSS (%) Miscarriage rate (%) Deliveries/cycle (%) Deliveries/transfer (%)
CO
CR
CO + CR
124 81 79 43 (34.7) 3796 ± 825 2213 ± 658a 11.9 ± 5.4c 3.3 ± 1.4 6 (4.8)a 1 (0.8)a 11/62 (18) 51/124 (41.1) 51/79 (65)d
19 19 19 n/a 2864 ± 810a 2864 ± 810 21.0 ± 9.8d 3.6 ± 0.7 15 (78.9)b 4 (21.0)b,e 0/8 (0) 8/19 (42.1) 8/19 (42.1)c
8 8 8 n/a 4108 ± 638b 3055 ± 599b 17.0 ± 3.8d 3.6 ± 1.5 5 (62.5)b 0 1/2 (50) 1/8 (12.5) 1/8 (12.5)c
Values are mean ± SD unless otherwise stated. a–dValues within rows followed by different superscript letters are significantly different (P < 0.05). eOne severe OHSS patient hospitalized.
graphical representation of oestradiol concentrations in cycles that proceeded to oocyte retrieval versus the cancelled cycles. The duration of coasting on outcome is presented in Table 2. In general, the higher the peak serum oestradiol concentration, the longer the coasting period. There was no significant difference in number of mature oocytes or pregnancy rates in patients who were coasted up to 4 days. None of the patients who were coasted for longer than 4 days underwent oocyte retrieval. The majority of these patients were cancelled due to large decreases in serum oestradiol concentrations. Two patients electively dropped out after their oestradiol concentrations remained >3000 pg/ml, despite being coasted for more than 4 days. The longest coast period was 8 days. Similarly, Ulug et al. (2002) recently reported lower implantation and pregnancy rates when coasting was necessary for 4 or more days. Cryopreservation was undertaken when the risk of OHSS was felt to be high. A small number of patients were coasted, underwent retrieval, and then had their embryos cryopreserved to prevent the development of OHSS. These groups are
compared with the coasted patients in Table 3. Statistical comparisons between the various groups were carried out via chi-squared analysis. Of note, the mean number of embryos transferred for each group did not significantly differ from other IVF patients not at risk for OHSS at Cornell over the same time period, which was 3.5 ± 1.1 embryos per transfer (mean ± SD). Table 3 shows that while coasting carried a significant risk of cancellation (34.7%), the overall delivery rate/started cycle was similar to the cryopreservation group. Although the number of mature oocytes was greater in the cryopreservation group, the delivery rate/transfer was higher in the coasting group. This probably reflects the advantage of fresh embryo transfer over frozen embryo transfer during that time period. The rate of OHSS observed in the coasted group was significantly lower. Although it appears that the coasting + cryopreservation group had the lowest delivery rate/transfer, this difference was not statistically significant from the cryopreservation group, a reflection of the small number of cycles in which both coasting and cryopreservation were performed. Indeed, the number of cycles in which only cryopreservation was performed is also
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quite small. These low numbers, combined with the retrospective nature of this analysis, limit our ability to draw many conclusions. However, the similar deliveries/cycle rate for the coasting group compared with the cryopreservation group is reassuring.
Conclusion The present approach to avoid OHSS is grounded in the training that Z.R. had in the mid to late 1970s under his mentors Howard and Georgeanna Jones at the Johns Hopkins Hospitals. It was their teaching and belief ‘that the key to reproductive medicine – and in the context of this paper, the avoidance of ovarian hyperstimulation syndrome – is an understanding of the underlying reproductive physiology’ (Jones and Jones, 1996). The primary approach should be identification of the patient at risk and individualization of stimulation protocols. Decreasing the magnitude of response to stimulation by using the lowest possible effective gonadotrophin dosage is the preferred approach.
References
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colloidal volume substitutes in severe ovarian hyperstimulation syndrome: a case report. European Journal of Obstetrics, Gynaecology and Reproductive Biology 99, 131–134. Konig E, Bussen S, Sutterlin M, Steck T 1998 Prophylactic intravenous hydroxyethyl starch solution prevents moderate–severe ovarian hyperstimulation in in-vitro fertilization patients: a prospective, randomized, double-blind and placebocontrolled study. Human Reproduction 13, 2421–2424. Lewit N, Kol S, Manor D, Itskovitz-Eldor J 1996 Comparison of gonadotropin-releasing hormone analogues and human chorionic gonadotrophin for the induction of ovulation and prevention of ovarian hyperstimulation syndrome: a case-control study. Human Reproduction 11, 1399–1402. Ludwig M, Felberbaum RE, Devroey P et al. 2000 Significant reduction of the incidence of ovarian hyperstimulation syndrome (OHSS) by using the LHRH antagonist cetrorelix in controlled ovarian stimulation for assisted reproduction. Archives of Gynecology and Obstetrics 264, 29–32. MacDougall MJ, Tan SL, Jacobs HS 1992 In vitro fertilization and the ovarian hyperstimulation syndrome. Human Reproduction 7, 579–600. McClure N, Healy DL, Rogers PAW et al. 1994 Vascular endothelial growth factor as capillary permeability agent in ovarian hyperstimulation syndrome. Lancet 344, 235–236. Medical Research International, Society for Assisted Reproductive Technology (SART), the American Fertility Society 1992 In vitro fertilization–embryo transfer (IVF–ET) in the United States: 1990 results from the IVF–ET registry. Fertility and Sterility 57, 15–24. Morris RS, Paulson RJ, Sauer MV, Lobo RA 1995 Predictive value of serum estradiol concentrations and oocyte number in severe ovarian hyperstimulation syndrome. Human Reproduction 10, 811. Navot D, Bergh P, Laufer N 1992 Ovarian hyperstimulation syndrome in novel reproductive technologies: prevention and treatment. Fertility and Sterility 58, 249–261. Ndukwe G, Dowell K, Thornton S et al. 1997 Severe ovarian hyperstimulation syndrome: is it really preventable by prophylactic intravenous albumin? Fertility and Sterility 68, 851–854. Neulan J, Yan Z, Raczek S et al. 1995 Human chorionic gonadotropin-dependent expression of vascular endothelial growth factor/vascular permeability factor in human granulosa cells: importance in ovarian hyperstimulation syndrome. Journal of Clinical Endocrinology and Metabolism 80, 1967–1971. Oppenheim JJ, Ruscetti FW, Faltynek C 1991 Cytokines. Basic and Clinical Immunology, 7th edn, Appleton and Lange, East Norwalk, Connecticut, pp. 78–100. Orvieto R, Ben-Rafael Z 1998 Ovarian hyperstimulation syndrome: a new insight into an old enigma. Journal of the Society for Gynecological Investigation 5, 110–113. Orvieto R, Voliovitch I, Fishman P et al. 1995 Interleukin-2 and ovarian hyperstimulation syndrome: a pilot study. Human Reproduction 10, 24–27. Pattinson HA, Highett M, Dunphy BC et al. 1994 Outcome of thaw embryo transfer after cryopreservation of all embryos in patients at risk of ovarian hyperstimulation syndrome. Fertility and Sterility 62, 1192. Queenan JT Jr, Veeck LL, Toner JP et al. 1997 Cryopreservation of all prezygotes in patients at risk of severe hyperstimulation does not eliminate the syndrome, but the chances of pregnancy are excellent with subsequent frozen–thaw transfers. Human Reproduction 12, 1573. Reljic M, Vlaisavljevic V, Gavricx V 1999 Number of oocytes retrieved and resulting pregnancy – risk factors for ovarian hyperstimulation syndrome. Journal of Reproductive Medicine 44, 713–718. Society of Assisted Reproduction Techniques (SART) Registry 1992 Assisted Reproductive Technology in the United States: 1992. Results generated from the American Society for Reproductive
medicine. Tiitinen A, Husa LM, Tulppala M et al. 1995 The effect of cryopreservation in prevention of ovarian hyperstimulation syndrome. British Journal of Obstetrics and Gynaecology 102, 326–329. Tomazevic T, Vrtovec HM 1996 Early timed follicular aspiration prevents severe ovarian hyperstimulation syndrome. Journal of Assisted Reproduction and Genetics 13, 282–286. Tortoriello DV, McGovern PG, Colon JM 1998 ‘Coasting’ does not adversely affect outcome in a subset of highly responsive in vitro fertilization patients. Fertility and Sterility 69, 454–460. Ulug U, Bahceci M, Erden H et al. 2002 The significance of coasting duration during ovarian stimulation for conception in assisted fertilization cycles. Human Reproduction 17, 310–317. Urman B, Pride SM, Yuen BH 1992 Management of overstimulated gonadotrophin cycles with a controlled drift period. Human Reproduction 7, 213–217. Wada I, Matson PL, Troup SA et al. 1990 Ovarian hyperstimulation syndrome in GnRH-a/hMG cycles for IVF and GIFT. Journal of Obstetrics and Gynecology 11, 88–89. Whelan JG, Vlahos NF 2000 The ovarian hyperstimulation syndrome. Fertility and Sterility 73, 883–895. Paper based on a contribution presented at the Serono Symposium ‘Towards Optimizing ART: a Tribute to Howard and Georgeanna Jones’ in Williamsburg, Virginia, USA, April 2002. Received 23 December 2002; refereed 14 February 2003; accepted 24 March 2003.
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Article Ovarian hyperstimulation syndrome: strategies for prevention Zev Rosenwaks, MD, is Director of The Center for Reproductive Medicine and Infertility, world-renowned infertility clinic at New York Weill Cornell. He is Professor of Obstetrics and Gynecology at Weill Medical College of Cornell University and was appointed the Revlon Distinguished Professor of Reproductive Medicine in Obstetrics and Gynecology in 1994. Dr Rosenwaks is a diplomate of the American Board of Obstetrics and Gynecology and received his subspecialty certification in Reproductive Endocrinology in 1981. He is a noted world authority on reproductive endocrinology and infertility and one of the founding pioneers in the assisted reproductive technologies. He has authored over 300 scientific papers, 45 book chapters and five textbooks. Dr Zev Rosenwaks Dehan Chen, Lynn Burmeister, Dan Goldschlag, Zev Rosenwaks1 The Center for Reproductive Medicine and Infertility, Weill Cornell Medical College, 505 East 70th Street, HMT-340, New York, NY 10021, USA 1Correspondence: e-mail: [email protected]
Abstract Ovarian hyperstimulation syndrome (OHSS) is a serious, iatrogenic complication of ovarian stimulation. The following report is a review of traditional and new strategies to prevent the development of OHSS. Techniques such as reducing the ovarian stimulus, coasting and cryopreservation are discussed. Other more investigative strategies are also summarized, including follicular aspiration, in-vitro maturation of immature oocytes, the use of gonadotrophin-releasing hormone (GnRH) agonists to trigger ovulation and the use of volume expanders such as hydroxyethyl starch. In addition, a review of the internal experience with OHSS at the authors’ institution is described. All these preventative approaches are based on current understanding of the physiologic mechanisms involved in the pathogenesis of OHSS.
Keywords: coasting, cryopreservation, IVF, OHSS, ovarian hyperstimulation
Introduction Ovarian hyperstimulation syndrome (OHSS) is a serious and potentially life-threatening complication of ovarian stimulation. Typically, the syndrome is seen in women who undergo ovulation induction with exogenous gonadotrophins, but it can also be seen rarely after administration of clomiphene citrate. The incidence of OHSS has been reported to be as high as 33%, with severe OHSS occurring in 0.5–4% of patients (Navot et al., 1992; Beerendonk et al., 1998; Enskog et al., 1999; Whelan and Vlahos, 2000). Although the incidence of severe OHSS is relatively low, it can result in significant morbidity and, rarely, even death. Generally, OHSS is preceded by multiple follicular development combined with a high serum oestradiol concentration. Luteinization is essential for its development. The early form occurs 3–7 days after human chorionic gonadotrophin (HCG) administration, while the late form of OHSS occurs 12–17 days after HCG administration. As clinical resolution usually parallels the decrease in residual concentrations of exogenous HCG, successful pregnancy with subsequent increase in endogenous HCG may account for the late form of OHSS. It is unclear whether women who present
with the so-called late forms also exhibit subclinical manifestation earlier in the luteal phase. Multiple pregnancy is also a risk factor for the late form of OHSS (Beerendonk et al., 1998). Ovarian enlargement and increased capillary permeability leading to a ‘third-space’ fluid shift characterize OHSS. These changes may cause haemoconcentration, electrolyte disturbances, liver and kidney dysfunction and thromboembolic sequelae. Physical symptoms primarily consist of distended abdomen, gastrointestinal discomfort, dyspnoea and decreased urine output. Clinical signs may include the following: rapid weight gain, oliguria, haemoconcentration, leukocytosis, hypovolaemia, electrolyte imbalance, ascites, pleural and pericardial effusion, adult respiratory distress syndrome, hypercoagulability and multiple organ failure. Death is rarely reported in the literature (Whelan and Vlahos, 2000). Treatment consists of supportive care and maintenance of vascular space integrity. Clinical signs and symptoms such as weight gain, changes in abdominal girth and haemoconcentration are useful to monitor clinical progression. Severe OHSS often requires hospitalization and medical
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intervention. Intravenous fluid (normal saline) and plasma expanders, such as albumin, may be useful in maintaining intravascular volume, and anticoagulation may be necessary to prevent thrombosis. Periodic paracentesis and rarely pleurocentesis may be employed to relieve physical discomfort, as well as to alleviate renal and respiratory compromise. Fortunately, OHSS is self-limiting and if pregnancy does not occur, recovery often begins at the end of the luteal phase. However, if pregnancy occurs, the time course of the disease may be as long as several weeks, presumably until the luteotrophic drive by endogenous HCG diminishes at 7–10 weeks gestation (Grudzinskas and Egbase, 1998).
Pathophysiology Morbidity in OHSS is primarily associated with a shift of intravascular fluid to the third space. This shift is believed to occur secondary to an elevation of factors that increase vascular permeability, which presumably rise as a consequence of exposure to the ovulatory stimulus. It is of relevance to note that exposure to HCG is most often responsible (or even obligatory) for the development of OHSS. Moreover, it has been observed that the LH surge elicits an inflammatory reaction, resulting in follicular wall breakdown and oocyte release, the intermediates of which have been implicated in the aetiology of OHSS. Thus, it should come as no surprise that increased concentrations of inflammatory cytokines such as interleukin (IL)-1, IL-2 and IL-6, along with an increase in vascular endothelial growth factor (VEGF), are associated with severe forms of this syndrome. Indeed, infusion of IL-2 into healthy subjects leads to the ‘vascular leak syndrome’, with the rapid accumulation of extravascular fluid resulting in ascites and pulmonary oedema (Oppenheim et al., 1991). HCG production has been shown to stimulate IL-2 from granulosa cells, and patients who develop severe OHSS have higher IL-2 concentrations in follicular fluid and serum compared with those who do not develop this syndrome, despite similar oestradiol concentrations and number of follicles (Orvieto et al., 1995). Additional evidence that these factors may be responsible for the syndrome comes from the observation that VEGF mRNA is highly correlated to HCG exposure in a dose- and time-dependant manner (Neulan et al., 1995). VEGF is known to increase endothelial cell permeability. VEGF mRNA is expressed in luteinized granulosa cells and has also been shown to be associated with OHSS. Moreover, infusion of anti-serum to VEGF leads to a 70% reduction in capillary leakage (McClure et al., 1994). The ovarian renin–angiotensin system has also been implicated as a putative mediator for OHSS development. Indeed, high renin concentrations are correlated with the severity of OHSS. Further studies may elucidate the specific roles of cytokines (IL-1, IL-6, IL-8, tumour necrosis factor (TNF) α), histamine, and prostaglandins in the pathophysiology of OHSS (Golan et al., 1989; Orvieto and Ben-Rafael, 1998).
Risk factors
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Prevention of OHSS relies principally on identifying patients at risk and individualization of stimulation protocols. Risk factors predisposing to OHSS include polycystic ovarian disease (PCOD), young age, history of previous OHSS and
low body weight. Patterns and response to ovarian stimulation may also provide clues as to susceptibility to OHSS. For example, the development of a large cohort of antral follicles associated with high and rapidly increasing oestradiol concentrations >3000 pg/ml on day of HCG, more than 20 follicles seen on ultrasound in the late follicular phase and greater than 15 oocytes retrieved, are all potential risk factors (Morris et al., 1995; Enskog et al., 1999; Reljic et al., 1999).
Prevention strategies Ovarian stimulation Women with exaggerated responses to gonadotrophins and particularly women with PCOD represent the greatest challenge. It is necessary to establish each individual’s FSH threshold dose, since exceeding this threshold may lead to excessive multifollicular development, thus increasing the risk for OHSS. It is therefore useful, in this highly susceptible group, to begin stimulation with relatively lower gonadotrophin doses, and then carefully titrate. Often this subgroup benefits from dual suppression with oral contraceptives and GnRH agonists, along with relatively low gonadotrophin doses (Damario et al., 1997). Careful monitoring of serum oestradiol concentrations with ultrasonographic assessment of follicle size and number helps to identify patients at risk. When possible, after establishing a given gonadotrophin threshold and achieving critical oestradiol concentrations (~200–300 pg/ml) and several follicles of 11–12 mm size, an attempt should be to step down gonadotrophin dosages. This approach allows the ≥12 mm follicles to continue to develop in a relatively low FSH milieu while theoretically ‘starving’ the smaller follicles. The net impact of such an approach results in fewer intermediate and small follicles on HCG day, thus theoretically reducing the risk of OHSS. Furthermore, as HCG is a risk factor for OHSS, it seems prudent to reduce the magnitude of this stimulus when possible. This can be accomplished by withholding or reducing the ovulatory dose of HCG. The customary dose of HCG is 10,000 IU; however, some authors advocate reducing the dose of HCG to trigger ovulation (Abdalla et al., 1997). We also employ this method to help reduce the incidence of OHSS; women with oestradiol concentrations exceeding 2000 pg/ml receive between 3300 and 5000 IU of HCG. Lowering the dose of HCG does not appear to affect oocyte quality or pregnancy rates. The administration of HCG is withheld or delayed when oestradiol concentrations exceed 3000 pg/ml.
Coasting Coasting refers to withholding gonadotrophins in individuals who exhibit extremely high oestradiol concentrations (>3000 pg/ml) and delaying HCG administration until oestradiol concentrations decrease, usually to concentrations between 2000 and 2500 pg/ml. This is an attractive alternative to cycle cancellation and appears to reduce the risk of OHSS. This approach may reduce the number of intermediate and small follicles by virtue of removing the FSH stimulus required to maintain their continued growth. The net reduction of small and intermediate follicles presumably reduces the overall
Articles - Prevention strategies for OHSS - D Chen et al.
release of potential OHSS inducing intermediates following HCG administration, thus reducing OHSS risk without reducing pregnancy success. The risk of coasting includes a reduction in the number of mature oocytes retrieved and a reduction in oocyte quality (Urman et al., 1992; Dhont et al., 1998; Tortoriello et al., 1998; Fluker et al., 1999). Retrieval should be cancelled if oestradiol concentrations drop by more than 20% after HCG administration, as oocyte quality and pregnancy rates are generally poor when such a pattern is observed (Benadiva et al., 1997).
Cryopreservation Oocyte retrieval and cryopreservation of all ensuing embryos is another alternative to cycle cancellation, since pregnancy and rising endogenous HCG titres exacerbate the risk for developing OHSS. This concept was confirmed by Morris et al. (1995), who noted that oocyte donors, who themselves did not become pregnant, had a very low risk for developing OHSS despite high oestradiol concentrations (>4000 pg/ml) after ovarian stimulation. Thus, for individuals who are at high risk for developing OHSS (i.e. oestradiol >3000 pg/ml and ≥20 oocytes retrieved), consideration could be given to avoiding fresh transfer in the cycle of retrieval with cryopreservation of all embryos (Egbase, 2000). If OHSS is felt to be imminent at the time of retrieval or shortly thereafter, embryos can be frozen at the pronuclear stage. The decision as to whether to cryopreserve all embryos can also be made based on clinical progression while waiting for day 5 (blastocyst) transfer. Fresh transfer should occur if no obvious signs or symptoms of OHSS are observed. Another strategy is to freeze a cohort of pronuclear embryos while allowing the rest of the embryos to progress to the blastocyst stage. Such decisions are usually based on an individual institution’s experience and success rates with pronuclear freezing, blastocyst culture, and blastocyst freezing. There have been several reports confirming that subsequent cryopreserved–thawed embryo transfers in such cycles yield reasonable pregnancy rates (Pattinson et al., 1994; Tiitinen et al., 1995; Queenan et al., 1997; Feraretti et al., 1999).
Intravenous albumin administration Several investigators have proposed that the prophylactic use of albumin, administered during and or after oocyte retrieval, may diminish the incidence of OHSS. This is accomplished presumably by maintaining intravascular oncotic pressure and decreasing third space fluid loss. It has also been postulated that albumin may bind putative intermediates which increase capillary permeability (Navot et al., 1992). Chen et al. (1997) concluded that intravenous administration of albumin after oocyte retrieval may prevent the development of severe OHSS in patients who either did not conceive or who had singleton pregnancies. However, they did not show that the use of albumin decreased the risk of OHSS in patients with highorder pregnancies. Alboulghar et al. (2000), in a meta-analysis of three randomized studies, concluded that IV albumin administration helps to reduce the incidence of severe OHSS. However, other investigators have not been able to confirm its efficacy (Ndukwe et al., 1997; Ben-Chetrit et al., 2001). Additional multicentre randomized controlled trials with larger numbers are still needed to determine if IV albumin can actually prevent severe OHSS in high-risk patients.
Intravenous hydroxyethyl starch administration Hydroxyethyl starch (HES) is a plasma expander that has gained recent attention as an alternative to albumin in reducing the incidence of OHSS. Because HES is a non-biological substance, it avoids any potential concern about viral transmission that is present with albumin. Two prospective randomized controlled studies demonstrated the superiority of 6% HES in preventing the development of OHSS versus placebo (Konig et al., 1998; Gokmen et al., 2001). Gokmen et al. also concluded that HES was as effective as albumin in the prevention of OHSS. One report even suggested that HES was superior to human albumin in the treatment of severe OHSS in terms of duration of hospitalization, urine output and incidence of paracenteses (Abramov et al., 2001). However, these results were contradicted in another study (Gamzu et al., 2002). While HES is considered to be well tolerated, one case report illustrated the dangers of over-infusion of HES (Kissler et al., 2001). In this case report, a patient was given large amounts of HES for 10 days to treat her severe OHSS. Well after her apparent recovery, the patient developed a pleural effusion and altered blood coagulation parameters. Analysis of the pleural effusion revealed a high concentration of HES leading to speculation that the loss of HES into the third space actually prolonged and aggravated the clinical course of OHSS.
Gonadotrophin-releasing hormone (GnRH) agonists/antagonists Typically, HCG is used as the surrogate to LH for oocyte maturation and ovulation induction in women undergoing ovarian stimulation. Given its longer half-life (>24 h versus 60 min for LH), HCG administration results in a prolonged luteotrophic effect (Fauser et al., 2002). This sustained effect may further exacerbate the risk for developing OHSS. An alternative to HCG-induced ovulation is the use of GnRH agonists. GnRH agonists can induce a sustained (>24 h) release of LH (and FSH) from the pituitary that can effectively induce oocyte maturation and ovulation (Lewit et al., 1996). However, the major limitation to its use is that GnRH agonists are ineffective in women who have a low endogenous gonadotrophin reserve or when suppressed by pituitary downregulation with GnRH agonists. Itskovitz-Eldor et al. (2000) overcame this problem by using GnRH antagonists to suppress ovulation during stimulation and showed that ovulation could then be effectively triggered with GnRH agonist. They concluded that the use of GnRH agonist to trigger ovulation is an effective way of stimulating ovulation in the high-responder whilst potentially reducing the risk of OHSS. Furthermore, GnRH antagonists can also be used to alleviate the development of OHSS in patients at high risk by blocking endogenous stimulation of the ovary (de Jong et al., 1998). Other authors have also concluded that the use of GnRH antagonists to suppress ovulation is associated with a lower risk of developing OHSS when compared with GnRH agonist cycles (Ludwig et al., 2000). Further trials are needed to confirm these observations.
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Recombinant human LH Recombinant human LH (rhLH) is also a viable alternative to HCG as an ovulatory stimulus. In fact, rhLH may prove to be more ‘physiological’ than HCG, given the shorter half-life of rhLH versus HCG (1–5 h for rhLH versus >1 day for HCG). As prolonged stimulation of the corpora lutea is believed to be a key factor in the development of OHSS, the shorter effect of rhLH should be useful in avoiding OHSS. The European Recombinant LH Study Group found that a single dose of rhLH resulted in a highly significant reduction in OHSS compared with HCG (European Recombinant LH Study Group, 2001). At this time, however, rhLH is not yet widely available in the United States.
Follicular aspiration It has been suggested that follicular aspiration could potentially reduce the risk of OHSS. Surgically induced intrafollicular haemorrhage has a negative impact on the corpus luteum. In essence, the intraovarian mechanisms responsible for OHSS may be modified by surgical follicular aspiration and hence meticulous aspiration of all follicles should be performed (Navot, 1992). Follicular aspiration for IVF may remove the source of cytokines as well as VEGF and other factors implicated in the development of OHSS, thus reducing the risk of serious sequelae. Some investigators have performed early unilateral cyst aspiration in the attempt to avoid the development of OHSS; however, reports from these studies are conflicting (Tomazevic and Vrtovec, 1996; Egbase et al., 1997, 1999). To date, there has only been one report in which ovarian cyst aspiration in patients with severe OHSS was shown to decrease the progression of OHSS (Fakih and Bello, 1992).
In-vitro maturation of immature oocytes It has been proposed that, for women who are at high risk of OHSS, i.e. those with polycystic ovarian disease, avoiding or minimizing ovarian stimulation may be the most reasonable approach to avoid OHSS. This approach requires in-vitro maturation of immature oocytes (IVM) retrieved from nonstimulated or minimally stimulated ovaries. Child et al. (2001) and Cha and Chian (1998) have demonstrated that reasonable pregnancy rates can be achieved in these individuals following IVM. It should be emphasized, however, that IVM protocols have not achieved pregnancy rates that are comparable to rates following ovarian stimulation and IVF of mature oocytes.
Table 1. Incidence of OHSS. New York Presbyterian–Weill Cornell Medical Centre July 1997–December 2000. Number Cycles Retrievals OHSS (mild and moderate)a Severe OHSSb
aIncludes any patient that presented for evaluation of mild abdominal discomfort <7 days post-HCG. bThree severe OHSS patients hospitalized.
ovarian stimulation. The incidence of OHSS excluding patients with early onset complaints was 0.4%. There were only three cases of severe OHSS requiring hospitalization during this time period (0.00055% of cycles), and only one of these cases required paracentesis. The other two cases resolved spontaneously. In all three cases the patients were pregnant, and each of the patients went on to deliver children (two singletons, one set of twins). This retrospective review represents the largest data set analysed for OHSS incidence in IVF from one institution in the literature. The overall rate of OHSS at Cornell of 1.0% using the most liberal criteria for OHSS is on the low end of the reported incidence of 1–10% of IVF cycles (Forman et al., 1990; Wada et al., 1990; MacDougall et al., 1992). Similarly, the incidence of severe OHSS of 0.00055% at Cornell compared favourably with the reported incidence of 0.5–2% of IVF cycles (Forman et al., 1990; SART, 1992). Clearly, much of the reduction in OHSS can be attributed to an improved understanding and awareness of the risk factors involved with OHSS that has evolved over time. Outcomes after coasting or cryopreservation were also compared in patients at risk of developing OHSS over a 5-year period at Cornell. Patients were coasted when their serum oestradiol concentration was ≥3000 pg/ml, or when their ultrasound revealed numerous immature follicles (<16 mm in diameter) in conjunction with a rapidly increasing serum oestradiol concentration. Administration of HCG was withheld until the serum oestradiol concentration dropped below 3000 pg/ml. Oocyte retrieval was cancelled if the oestradiol concentration dropped ≥20% after HCG administration. Figure 1 is a
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Table 1 summarizes the incidence of OHSS during a 3.5-year period. Although 54 patients complained of symptoms (1% of cycles), most of the cases involved symptoms of mild abdominal discomfort that occurred less than 7 days after HCG administration, and resolved without further sequelae. Some argue that these early, mild cases do not represent true OHSS, but are part of the spectrum of anticipated symptoms from
Oestradiol (pg/ml)
The Cornell experience The total experience and incidence of OHSS following IVF at Cornell from July 1997 through December 2000 has been reviewed. Particular attention was given to the common OHSS prevention strategies and their impact on pregnancy outcome.
5409 4443 22 3
4500 4000 3500 3000
Cancelled Coast and transfer
2500 2000 1500 1000 500 0 Peak
On day of HCG
Post HCG
Figure 1. Oestradiol concentrations (pg/ml): cancelled coast cycles versus coast and transfer. Thirty-six coasted patients cancelled due to drop in oestradiol, two patients cancelled due to high oestradiol, five patients cancelled for other reasons.
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Table 2. Coasting interval.
No. retrievals/cycles (% cancelled) Peak oestradiol (pg/ml)a Oestradiol on HCG day (pg/ml)a Mature oocytes (n)a Embryos transferred (n)a Miscarriage rate (%) Deliveries/cycle (%) No. deliveries/transfer (%)
Number of days coasted 1 2
3
4
>4
35/42 (17)
34/48 (29)
13/22 (41)
7/12 (42)
0/8 (100)
3227 ± 800 2539 ± 736
3903 ± 610 2247 ± 702
4364 ± 778 1977 ± 633
4892 ± 904 1852 ± 725
5258 ± 1035 –
13.5 ± 4.8 3.7 ± 1.5 2/26 (8) 24/42 (57) 24/35 (69)
11.7 ± 5.2 2.8 ± 1.6 9/26 (35) 17/48 (35) 17/34 (50)
11.6 ± 6.9 2.0 ± 1.7 1/7 (14) 6/22 (27) 6/13 (46)
10.9 ± 6.4 2.7 ± 1.8 0/5 (0) 5/12 (42) 5/7 (71)
– – – – –
aMean ± SD.
Table 3. Coasting (CO) versus cryopreservation (CR). New York Presbyterian–Weill Cornell Medical Centre 1995–1999.
Cycles (n) Retrievals (n) Transfers (n) Cancellation rate (%) Peak oestradiol (pg/ml)a Oestradiol on HCG day (pg/ml)a Mature oocytesa Embryos transferreda Early onset symptoms (%) OHSS (%) Miscarriage rate (%) Deliveries/cycle (%) Deliveries/transfer (%)
CO
CR
CO + CR
124 81 79 43 (34.7) 3796 ± 825 2213 ± 658a 11.9 ± 5.4c 3.3 ± 1.4 6 (4.8)a 1 (0.8)a 11/62 (18) 51/124 (41.1) 51/79 (65)d
19 19 19 n/a 2864 ± 810a 2864 ± 810 21.0 ± 9.8d 3.6 ± 0.7 15 (78.9)b 4 (21.0)b,e 0/8 (0) 8/19 (42.1) 8/19 (42.1)c
8 8 8 n/a 4108 ± 638b 3055 ± 599b 17.0 ± 3.8d 3.6 ± 1.5 5 (62.5)b 0 1/2 (50) 1/8 (12.5) 1/8 (12.5)c
Values are mean ± SD unless otherwise stated. a–dValues within rows followed by different superscript letters are significantly different (P < 0.05). eOne severe OHSS patient hospitalized.
graphical representation of oestradiol concentrations in cycles that proceeded to oocyte retrieval versus the cancelled cycles. The duration of coasting on outcome is presented in Table 2. In general, the higher the peak serum oestradiol concentration, the longer the coasting period. There was no significant difference in number of mature oocytes or pregnancy rates in patients who were coasted up to 4 days. None of the patients who were coasted for longer than 4 days underwent oocyte retrieval. The majority of these patients were cancelled due to large decreases in serum oestradiol concentrations. Two patients electively dropped out after their oestradiol concentrations remained >3000 pg/ml, despite being coasted for more than 4 days. The longest coast period was 8 days. Similarly, Ulug et al. (2002) recently reported lower implantation and pregnancy rates when coasting was necessary for 4 or more days. Cryopreservation was undertaken when the risk of OHSS was felt to be high. A small number of patients were coasted, underwent retrieval, and then had their embryos cryopreserved to prevent the development of OHSS. These groups are
compared with the coasted patients in Table 3. Statistical comparisons between the various groups were carried out via chi-squared analysis. Of note, the mean number of embryos transferred for each group did not significantly differ from other IVF patients not at risk for OHSS at Cornell over the same time period, which was 3.5 ± 1.1 embryos per transfer (mean ± SD). Table 3 shows that while coasting carried a significant risk of cancellation (34.7%), the overall delivery rate/started cycle was similar to the cryopreservation group. Although the number of mature oocytes was greater in the cryopreservation group, the delivery rate/transfer was higher in the coasting group. This probably reflects the advantage of fresh embryo transfer over frozen embryo transfer during that time period. The rate of OHSS observed in the coasted group was significantly lower. Although it appears that the coasting + cryopreservation group had the lowest delivery rate/transfer, this difference was not statistically significant from the cryopreservation group, a reflection of the small number of cycles in which both coasting and cryopreservation were performed. Indeed, the number of cycles in which only cryopreservation was performed is also
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Articles - Prevention strategies for OHSS - D Chen et al.
quite small. These low numbers, combined with the retrospective nature of this analysis, limit our ability to draw many conclusions. However, the similar deliveries/cycle rate for the coasting group compared with the cryopreservation group is reassuring.
Conclusion The present approach to avoid OHSS is grounded in the training that Z.R. had in the mid to late 1970s under his mentors Howard and Georgeanna Jones at the Johns Hopkins Hospitals. It was their teaching and belief ‘that the key to reproductive medicine – and in the context of this paper, the avoidance of ovarian hyperstimulation syndrome – is an understanding of the underlying reproductive physiology’ (Jones and Jones, 1996). The primary approach should be identification of the patient at risk and individualization of stimulation protocols. Decreasing the magnitude of response to stimulation by using the lowest possible effective gonadotrophin dosage is the preferred approach.
References
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