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Prevention and management of ovarian hyperstimulation syndrome

Chin-Der Chen MD, Shee-Uan Chen MD and Yu-Shih Yang MD, PhD

Published online Jun-2013, pages 817 - 827


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Steps to minimise risk

The prevention of OHSS includes three main strategies: identification of women at risk, using different ovulation-induction strategies before stimulation, and preventive therapy modalities during stimulation (Table 1). The combined use of a gonadotrophin-releasing hormone (GnRH) antagonist protocol with GnRH agonist triggering and oocyte and embryo freezing has considerable promise in preventing OHSS.23 x J.A. Garcia-Velasco. Agonist trigger: what is the best approach? Agonist trigger with vitrification of oocytes or embryos. Fertil Steril. 2012;97:527-528 Crossref.

Table 1 Strategies for preventing ovarian hyperstimulation syndrome.

Identification of women at risk
Using different ovulation-induction strategies Individually tailored gonadotrophin regimen
GnRH antagonist protocol
In-vitro maturation
Metformin
Preventive therapy modalities during stimulation Cycle cancellation
Coasting (withholding gonadotrophins)
Administration of intravenous albumin and hydroxyethyl starch
Triggering ovulation by low-dose of hCG
GnRH agonist to trigger final oocyte maturation
Avoidance of hCG for luteal support
Cryopreservation of all oocytes and embryos
Dopamine agonist therapy
Low-dose aspirin therapy

References in context

  • The prevention of OHSS includes three main strategies: identification of women at risk, using different ovulation-induction strategies before stimulation, and preventive therapy modalities during stimulation (Table 1).
    Go to context

GnRH, gonadotrophin-releasing hormone; hCG, human chorionic gonadotrophin.

Identification of women at risk

Recognising risk factors of OHSS is the key to prevention. All women undergoing ovarian stimulation should be considered at risk of OHSS. Women at higher risk of developing OHSS include young age, low body weight, polycystic ovary syndrome (PCOS), use of GnRH agonists, higher doses of exogenous gonadotrophins, high absolute or rapidly rising serum oestradiol levels, development of multiple follicles during treatment, exposure to hCG, and previous episodes of OHSS.17 and 18 x Royal College of Obstetricians and Gynaecologists (RCOG). The management of ovarian hyperstimulation syndrome, Green-top guideline, number 5. (RCOG, London, 2006) 1–11 x Practice Committee of American Society for Reproductive Medicine (ASRM). Ovarian hyperstimulation syndrome. Fertil Steril. 2008;90:S188-S193 Pregnancy increases the likelihood, duration, and severity of OHSS symptoms. An earlier study had reported an OHSS rate of 37% in women with PCOS, whereas the rate was 15% in women without PCOS.10 x A. Delvigne, A. Demoulin, J. Smitz, et al. The ovarian hyperstimulation syndrome in in-vitro fertilization: a Belgian multicentric study. I. Clinical and biological features. Hum Reprod. 1993;8:1353-1360 Ovarian stimulation in women with PCOS needs to be individually tailored and closely monitored.

A systematic review and meta-analysis of the existing literature24 x S.L. Broer, M. Dólleman, B.C. Opmeer, et al. AMH and AFC as predictors of excessive response in controlled ovarian hyperstimulation: a meta-analysis. Hum Reprod Update. 2011;17:46-54 Crossref. showed that both anti-Müllerian hormone and antral follicle count are accurate predictors of excessive response to ovarian hyperstimulation. Measurement of basal serum anti-Müllerian hormone and antral follicle count can be used to determine the women who are high risk for OHSS.25 and 26 x T.H. Lee, C.H. Liu, C.C. Huang, et al. Serum anti-Müllerian hormone and estradiol levels as predictors of ovarian hyperstimulation syndrome in assisted reproduction technology cycles. Hum Reprod. 2008;23:160-167 x P. Ocal, S. Sahmay, M. Cetin, et al. Serum anti-Müllerian hormone and antral follicle count as predictive markers of OHSS in ART cycles. J Assist Reprod Genet. 2011;28:1197-1203 Crossref.

Using different ovulation-induction strategies

Individually tailored gonadotrophin regimen

Gonadotrophins can be used for induction of ovulation in anovulatory women or ovarian stimulation for intrauterine insemination or IVF. The differences in the objectives of these three forms of treatment were single follicle for induction of ovulation in anovulatory women, two to three follicles in intrauterine insemination and six to 10 follicles in IVF. Ovarian hyperstimulation syndrome can occur in both induction of ovulation and ovarian stimulation for assisted reproduction. The choice of the gonadotrophin starting dose is an important parameter to prevent the onset of OHSS. It is recognised that reducing the starting dose to 100 IU follicle-stimulating hormone (FSH) or even 75 IU per day in high-risk women could minimise the risk of OHSS.27 x F. Olivennes. Ovarian hyperstimulation syndrome prevention strategies: individualizing gonadotrophin dose. Semin Reprod Med. 2010;28:463-467 Crossref. Unfortunately, the syndrome may occur even in women who receive small starting doses.28 x A. Enskog, M. Henriksson, M. Unander, et al. Prospective study of the clinical and laboratory parameters of patients in whom ovarian hyperstimulation syndrome developed during controlled ovarian hyperstimulation for in vitro fertilization. Fertil Steril. 1999;71:808-814 Crossref.

The basis of the classic chronic, low-dose, step-up protocol is to identify the threshold dose that is necessary to induce follicular maturation, especially in women suffering from PCOS.29 x R. Homburg, C.M. Howles. Low-dose FSH therapy for anovulatory infertility associated with polycystic ovary syndrome: rationale, results, reflections and refinements. Hum Reprod Update. 1999;5:493-499 Crossref. The protocol normally starts with a dose of 75 IU daily for 14 days, followed by small stepwise increases (37.5 IU or less) for a period of 7 days. The dose can again be increased after this period if there is no response. Chronic low-dose step-up gonadotrophin is more useful for induction of ovulation.

The aim of the step-down protocol30 x E.J. van Santbrink, B.C. Fauser. Urinary follicle-stimulating hormone for normogonadotropic clomiphene-resistant anovulatory infertility: prospective, randomized comparison between low dose step-up and step-down dose regimens. J Clin Endocrinol Metab. 1997;82:3597-3602 is to rapidly achieve the FSH threshold for stimulating follicle development, and thus step-down regimens normally begin with a dose of 150 IU FSH daily followed by reduction of the dose once the initial response is established. Both low-dose, step-up and step-down protocols have been shown to help reduce the risk of over-response associated with a lower incidence of OHSS.31 x Thessaloniki ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Consensus on infertility treatment related to polycystic ovary syndrome. Hum Reprod. 2008;23:462-477

The use of the gonadotrophin-releasing hormone antagonist protocol

The use of GnRH antagonist protocol resulted in a more physiological approach to ovarian stimulation, leading to fewer side-effects and complications than the long-agonist protocol. Additionally, when using GnRH antagonist protocol, one may induce oocyte maturation with GnRH agonists. This issue will be discussed later. A Cochrane review32 x H.G. Al-Inany, M.A. Youssef, M. Aboulghar, et al. Gonadotrophin-releasing hormone antagonists for assisted reproductive technology. Cochrane Database Syst Rev. 2011;5:CD001750 concluded that the use of antagonist compared with long GnRH agonist protocols was associated with a large reduction in OHSS, with no evidence of a difference in live-birth rates. The data, however, are inconclusive from a recent systematic review and meta-analysis,33 x J. Pundir, S.K. Sunkara, T. El-Toukhy, et al. Meta-analysis of GnRH antagonist protocols: do they reduce the risk of OHSS in PCOS?. Reprod Biomed Online. 2012;24:6-22 Crossref. which investigated whether GnRH antagonist protocols reduce the risk of OHSS in women with PCOS undergoing IVF compared with the long agonist protocol. This review included nine randomised-controlled trials (RCTs) with a total of 966 women with PCOS, and showed no significant difference in the incidence of severe OHSS with the antagonist group compared with the long-agonist group. The incidence of moderate and severe OHSS, when combined together, is reduced with the GnRH antagonist protocol compared with the GnRH long agonist protocol.

In-vitro maturation of oocytes

Although the pregnancy and implantation rates of in-vitro maturation (IVM) treatment are not as high as conventional IVF treatment, immature oocyte retrieval followed by IVM is a promising potential treatment option for infertile women with PCOS, because this group of women are extremely sensitive to stimulation with exogenous gonadotrophins and is at increased risk of developing OHSS.34 x J.Y. Huang, R.C. Chian, S.L. Tan. Ovarian hyperstimulation syndrome prevention strategies: in vitro maturation. Semin Reprod Med. 2010;28:519-531 Crossref. It has been shown that priming with FSH or hCG before immature oocyte retrieval improved oocyte maturation and pregnancy rates.35 x J.E.J. Smitz, J.G. Thompson, R.B. Gilchrist. The promise of in vitro maturation in assisted reproduction and fertility preservation. Semin Reprod Med. 2011;29:24-37 Therefore, IVM treatment represents an attractive alternative to cycle cancellation, coasting, or embryo cryopreservation.

Metformin

In women with PCOS, short-term treatment with metformin did not improve the response to stimulation but it did improve the pregnancy outcome and reduced the incidence of OHSS.36 x T. Tang, J. Glanville, N. Orsi, et al. The use of metformin for women with PCOS undergoing IVF treatment. Hum Reprod. 2006;21:1416-1425 Crossref. A meta-analysis of RCTs showed that the administration of metformin significantly reduced the risk of OHSS.37 x L.O. Tso, M.F. Costello, L.E. Albuquerque, et al. Metformin treatment before and during IVF or ICSI in women with polycystic ovary syndrome. Cochrane Database Syst Rev. 2009;15:CD006105 These findings were obtained from four RCTs that included 449 participants with PCOS who were scheduled for IVF cycles. A recent large RCT found that metformin effectively reduces the incidence of OHSS in a high-risk population of women with PCOS who are receiving gonadotrophin for IVF.38 x S. Palomba, A. Falbo, L. Carrillo, et al. Metformin reduces risk of ovarian hyperstimulation syndrome in patients with polycystic ovary syndrome during gonadotrophin-stimulated in vitro fertilization cycles: a randomized, controlled trial. Fertil Steril. 2011;96:1384-1390.e4 The action of metformin is still unknown.

Preventive therapy modalities during stimulation

Cycle cancellation

When symptoms of OHSS emerge even before administration of hCG, cycle cancellation should be seriously considered. Cycle cancellation and withholding of hCG is the only guaranteed method for preventing early OHSS.39 x R.G. Forman, R. Frydman, D. Egan, et al. Severe ovarian hyperstimulation syndrome using agonists of gonadotrophin-releasing hormone for in vitro fertilization: a European series and a proposal for prevention. Fertil Steril. 1990;53:502-509 At present, it is less widely used because of the development of the more acceptable strategies such as coasting.

Coasting (withholding gonadotrophins)

Withholding further gonadotrophin stimulation and delaying hCG administration until oestradiol levels plateau or decrease significantly can reduce risks of OHSS.40 x A. Delvigne, S. Rozenberg. A qualitative systematic review of coasting, a procedure to avoid ovarian hyperstimulation syndrome in IVF patients. Hum Reprod Update. 2002;8:291-296 Crossref. Coasting does not eliminate the risk of OHSS but may reduce the incidence and severity of the condition. According to a recent Cochrane review,41 x A. D'Angelo, J. Brown, N.N. Amso. Coasting (withholding gonadotrophins) for preventing ovarian hyperstimulation syndrome. Cochrane Database Syst Rev. 2011;6:CD002811 no evidence suggested a benefit of using coasting to prevent OHSS compared with no coasting or other interventions. The Cochrane review included only four studies. Their conclusions were based on heterogeneous studies, and these results have to be interpreted with caution.

Initiating coasting depends on both oestradiol levels and numbers and size of follicles.42 x C.D. Chen, K.H. Chao, J.H. Yang, et al. Comparison of coasting and intravenous albumin in the prevention of ovarian hyperstimulation syndrome. Fertil Steril. 2003;80:86-90 Crossref. It is generally accepted that coasting should be initiated when the oestradiol level is greater than 3000 pg/mL in the setting of numerous immature follicles (<16 mm) with rapidly increasing oestradiol level.43 and 44 x R. Abdallah, I. Kligman, O. Davis, et al. Withholding gonadotrophins until human chorionic gonadotrophin administration. Semin Reprod Med. 2010;28:486-492 Crossref. x J.A. Garcia-Velasco, V. Isaza, G. Quea, et al. Coasting for the prevention of ovarian hyperstimulation syndrome: much ado about nothing?. Fertil Steril. 2006;85:547-554 Crossref. Human chorionic gonadotrophin can be given when oestradiol levels drop to a ‘safe’ level (e.g. 3000 pg/mL). Such ‘coasting’ does not adversely affect outcome in IVF cycles unless it is prolonged (more than 3 days). Cycle cancellation should be considered if the duration of coasting exceeds 4 days or if the oestradiol level decreases by more than 30% the day after hCG trigger.43 x R. Abdallah, I. Kligman, O. Davis, et al. Withholding gonadotrophins until human chorionic gonadotrophin administration. Semin Reprod Med. 2010;28:486-492 Crossref.

Administration of intravenous albumin and hydroxyethyl starch

Prophylactic intravenous administration of 25% albumin (20–50 g) at time of oocyte retrieval has been suggested as a means of reducing risk of OHSS. The most recent Cochrane meta-analysis46 x C.A. Venetis, E.M. Kolibianakis, K.A. Toulis, et al. Intravenous albumin administration for the prevention of severe ovarian hyperstimulation syndrome: a systematic review and metaanalysis. Fertil Steril. 2011;95:188-196 of eight RCTs suggested that there is limited evidence of benefit from intravenous albumin administration at the time of oocyte retrieval in the prevention or reduction of the incidence of severe OHSS in high-risk women undergoing IVF or intracytoplasmic sperm injection treatment cycles.45 x M.A. Youssef, H.G. Al-Inany, J.L. Evers, et al. Intra-venous fluids for the prevention of severe ovarian hyperstimulation syndrome. Cochrane Database Syst Rev. 2011;16:CD001302 Another system review and meta-analysis, however, suggested that intravenous albumin administration in high-risk women does not seem to reduce the occurrence of severe OHSS.46 x C.A. Venetis, E.M. Kolibianakis, K.A. Toulis, et al. Intravenous albumin administration for the prevention of severe ovarian hyperstimulation syndrome: a systematic review and metaanalysis. Fertil Steril. 2011;95:188-196

An alternative to human albumin is hydroxyethyl solution (1000 mL 6% at the time of oocyte retrieval, followed by another 500 mL 48 h later). A recent Cochrane meta-analysis of three RCTs involving 487 randomised women suggested that hydroxyethyl starch markedly decreases the incidence of severe OHSS.45 x M.A. Youssef, H.G. Al-Inany, J.L. Evers, et al. Intra-venous fluids for the prevention of severe ovarian hyperstimulation syndrome. Cochrane Database Syst Rev. 2011;16:CD001302

Triggering ovulation by low dose of human chorionic gonadotrophin

Although hCG has been the gold standard for ovulation triggering, it is responsible for an increased incidence of OHSS. To date, consensus is lacking over the optimal dose of hCG for final oocyte maturation. A systematic review of all studies that compared the effect of at least two doses of hCG for final oocyte maturation on IVF outcome and on the incidence of OHSS concluded that the clinical outcome were similar between women receiving 5000 or 10,000 IU hCG. The incidence of OHSS was not reduced in the high-risk population even with lower dose of urinary hCG.47 x I. Tsoumpou, J. Muglu, T.A. Gelbaya, et al. Symposium: update on prediction and management of OHSS. Optimal dose of HCG for final oocyte maturation in IVF cycles: absence of evidence?. Reprod Biomed Online. 2009;19:52-58 Crossref. Owing to the lack of concrete evidence, it is believed that the dose of hCG should be individualised in the same way as the starting dose of gonadotrophins. Good responders need not receive a dose higher than 5000 IU of hCG. A lower dose of hCG may be prudent for women judged to be at high risk for OHSS.18 x Practice Committee of American Society for Reproductive Medicine (ASRM). Ovarian hyperstimulation syndrome. Fertil Steril. 2008;90:S188-S193

Gonadotrophin-releasing hormone agonist to trigger final oocyte maturation

Gonadotrophin-releasing hormone agonist triggering is now a valid alternative to hCG triggering. Agonist triggering offers the possibility to individually tailor the luteal phase support according to the ovarian response to stimulation.48 x P. Humaidan. Agonist trigger: what is the best approach? Agonist trigger and low dose hCG. Fertil Steril. 2012;97:529-530 Crossref. Most recent studies have used single doses of the following types of GnRH agonist: either triptorelin 0.2 mg,49 x E.G. Papanikolaou, W. Verpoest, H. Fatemi, et al. A novel method of luteal supplementation with recombinant luteinizing hormone when a gonadotrophin-releasing hormone agonist is used instead of human chorionic gonadotrophin for ovulation triggering: a randomized prospective proof of concept study. Fertil Steril. 2011;95:1174-1177 Crossref. buserelin 0.5 mg,50 x P. Humaidan, H.E. Bredkjaer, L. Bungum, et al. GnRH agonist (buserelin) or hCG for ovulation induction in GnRH antagonist IVF/ICSI cycles: a prospective randomized study. Hum Reprod. 2005;20:1213-1220 Crossref. or leuprolide acetate 1.5 mg.51 x J.C. Castillo, M. Dolz, E. Bienvenido, et al. Cycles triggered with GnRH agonist: exploring low-dose HCG for luteal support. Reprod Biomed Online. 2010;20:175-181 Crossref. Most studies support supplementation with luteinising hormone activity in addition to standard luteal phase support with oestradiol and progesterone. Luteinising hormone activity could be supplemented in the form of either one bolus of 1500 IU hCG administered on the day of oocyte retrieval,52 x P. Humaidan, H.E. Bredkjaer, L.G. Westergaard, et al. 1500 IU human chorionic gonadotrophin administered at oocyte retrieval rescues the luteal phase when gonadotrophin-releasing hormone agonist is used for ovulation induction: a prospective, randomized, controlled study. Fertil Steril. 2010;93:847-854 Crossref. a total of three boluses of hCG (250–500 IU) during the luteal phase,51 x J.C. Castillo, M. Dolz, E. Bienvenido, et al. Cycles triggered with GnRH agonist: exploring low-dose HCG for luteal support. Reprod Biomed Online. 2010;20:175-181 Crossref. or recombinant luteinising hormone 300 IU administered every second day during the luteal phase until a positive pregnancy test.49 x E.G. Papanikolaou, W. Verpoest, H. Fatemi, et al. A novel method of luteal supplementation with recombinant luteinizing hormone when a gonadotrophin-releasing hormone agonist is used instead of human chorionic gonadotrophin for ovulation triggering: a randomized prospective proof of concept study. Fertil Steril. 2011;95:1174-1177 Crossref.

A recent meta-analysis showed that the modified luteal support has had a significant positive effect on the reproductive outcome after GnRH agonist triggering without an increase in the OHSS rate.53 x P. Humaidan, S. Kol, E. Papanikolaou. GnRH agonist for triggering of final oocyte maturation: time for a change of practice?. Hum Reprod Update. 2011;17:510-524 Crossref. Nevertheless, the most optimal luteal phase support still has to be explored. Until the optimal protocol of luteal supplementation is defined, an alterative option is to freeze all oocytes and embryos (so-call ‘freeze-all’) and transfer in subsequent natural or stimulated cycles.23 x J.A. Garcia-Velasco. Agonist trigger: what is the best approach? Agonist trigger with vitrification of oocytes or embryos. Fertil Steril. 2012;97:527-528 Crossref. The combination of agonist trigger and ‘freeze all’ gives maximum protection and may even result in better implantation. It results, however, in patient inconvenience and additional expense. GnRH agonist triggering should be used in all oocyte donation cycles, owing to a total elimination of OHSS.54 and 55 x M. Cerrillo, S. Rodríguez, M. Mayoral, et al. Differential regulation of VEGF after final oocyte maturation with GnRH agonist versus hCG: a rationale for OHSS reduction. Fertil Steril. 2009;91:1526-1528 Crossref. x M. Melo, C.E. Busso, J. Bellver, et al. GnRH agonist versus recombinant HCG in an oocyte donation programme: a randomized, prospective, controlled, assessor-blind study. Reprod Biomed Online. 2009;19:486-492 Crossref.

Avoidance of human chorionic gonadotrophin for luteal support

Luteal support with hCG is associated with a higher risk for OHSS and should be avoided.56 x M. van der Linden, K. Buckingham, C. Farquhar, et al. Luteal phase support for assisted reproduction cycles. Cochrane Database Syst Rev. 2011;5:CD009154 The use of exogenous progesterone (e.g. 50 mg progesterone in oil intramuscular, 100 mg progesterone vaginal suppositories, or 8% progesterone vaginal gel, daily) for luteal phase support rather than supplemental doses of hCG, may further reduce risks of OHSS.39 x R.G. Forman, R. Frydman, D. Egan, et al. Severe ovarian hyperstimulation syndrome using agonists of gonadotrophin-releasing hormone for in vitro fertilization: a European series and a proposal for prevention. Fertil Steril. 1990;53:502-509 When symptoms of OHSS emerge even before administration of hCG, cycle cancellation and less aggressive stimulation in a subsequent cycle should be seriously considered.

Cryopreservation of all oocytes and embryos

Administration of hCG to trigger ovulation followed by oocyte retrieval and elective freezing of all embryos will not avoid early OHSS but will prevent the development of the late form of OHSS. In a recently updated Cochrane review, however, there is insufficient evidence to support routine cryopreservation.57 x A. D'Angelo, N. Amso. Embryo freezing for preventing ovarian hyperstimulation syndrome. Cochrane Database Syst Rev. 2007;18:CD002806 The reviewers concluded that these results have to be interpreted with caution because of the small number of women in the individual studies. Many IVF centres continue to use this method as a way of reducing the risk of OHSS. More research is needed to determine whether using elective cryopreservation of embryos can reduce the rate of severe OHSS in IVF. The true value of cryopreservation for the prevention of OHSS during IVF, however, may be as an adjunct intervention in support of other effective rescue techniques rather than as a stand-alone option.58 and 59 x P. Humaidan, J. Quartarolo, E.G. Papanikolaou. Preventing ovarian hyperstimulation syndrome: guidance for the clinician. Fertil Steril. 2010;94:389-400 Crossref. x G. Griesinger, L. Schultz, T. Bauer, et al. Ovarian hyperstimulation syndrome prevention by gonadotrophin-releasing hormone agonist triggering of final oocyte maturation in a gonadotrophin-releasing hormone antagonist protocol in combination with a “freeze-all” strategy: a prospective multicentric study. Fertil Steril. 2011;95:2029-2033

Dopamine agonist therapy

The increase vascular permeability seen in OHSS is primarily caused by ovarian secretion of vascular endothelial growth factor, which activates its receptor (VEGFR-2). Administration of a dopamine or dopamine receptor 2 agonist, inactivates VEGFR-2 and prevents the increase in vascular permeability.60 x S. Basu, J.A. Nagy, S. Pal, et al. The neurotransmitter dopamine inhibits angiogenesis induced by vascular permeability factor/vascular endothelial growth factor. Nat Med. 2001;7:569-574 Crossref. Cabergoline 0.5 mg tablet daily starting on the day of hCG injection and continue for 8 days have been shown to reduce the risk of severe OHSS. Recently, a systematic review and meta-analysis of four randomised trials comparing the prophylactic effect of the dopamine agonist, cabergoline, versus no treatment in IVF and intracytoplasmic sperm injection cycles showed that prophylactic treatment with the dopamine agonist, cabergoline, reduces the incidence, but not the severity of OHSS, without compromising pregnancy outcomes.61 x M.A. Youssef, M. van Wely, M.A. Hassan, et al. Can dopamine agonists reduce the incidence and severity of OHSS in IVF/ICSI treatment cycles? A systematic review and meta-analysis. Hum Reprod Update. 2010;16:459-466 Crossref.

Low-dose aspirin therapy

Low-dose aspirin therapy for prevention of OHSS is based on the theory that superovulation treatment may induce platelet hyperstimulation, which is associated with OHSS, and that aspirin therapy may inhibit this effect. Recently, the low-dose aspirin treatment (100 mg daily, beginning on the first day of ovarian stimulation) was shown to reduce the risk of severe OHSS in a large randomised clinical trial.62 x A. Varnagy, J. Bodis, Z. Manfai, et al. Low-dose aspirin therapy to prevent ovarian hyperstimulation syndrome. Fertil Steril. 2009;93:2281-2284

 
x

Table 1 Strategies for preventing ovarian hyperstimulation syndrome.

Identification of women at risk
Using different ovulation-induction strategies Individually tailored gonadotrophin regimen
GnRH antagonist protocol
In-vitro maturation
Metformin
Preventive therapy modalities during stimulation Cycle cancellation
Coasting (withholding gonadotrophins)
Administration of intravenous albumin and hydroxyethyl starch
Triggering ovulation by low-dose of hCG
GnRH agonist to trigger final oocyte maturation
Avoidance of hCG for luteal support
Cryopreservation of all oocytes and embryos
Dopamine agonist therapy
Low-dose aspirin therapy

References in context

  • The prevention of OHSS includes three main strategies: identification of women at risk, using different ovulation-induction strategies before stimulation, and preventive therapy modalities during stimulation (Table 1).
    Go to context

GnRH, gonadotrophin-releasing hormone; hCG, human chorionic gonadotrophin.

References

Label Authors Title Source Year
10

References in context

  • An earlier study had reported an OHSS rate of 37% in women with PCOS, whereas the rate was 15% in women without PCOS.10 Ovarian stimulation in women with PCOS needs to be individually tailored and closely monitored.
    Go to context

A. Delvigne, A. Demoulin, J. Smitz, et al. The ovarian hyperstimulation syndrome in in-vitro fertilization: a Belgian multicentric study. I. Clinical and biological features Hum Reprod. 1993;8:1353-1360 1993
*18

References in context


  • Go to context

  • The Practice Committee of the American Society for Reproductive Medicine proposed a simplified classification of the syndrome into mild, worsening, and serious.18 Progression of illness is recognised when symptoms persist, worsen, or include ascites that may be demonstrated by increasing abdominal girth or ultrasound evaluation.
    Go to context

  • Although hCG has been the gold standard for ovulation triggering, it is responsible for an increased incidence of OHSS.
    Go to context

  • Rapid initial hydration may be accomplished with bolus of intravenous fluid (1000 ml normal saline) to maintain adequate urine output and reverse haemoconcentration.63 If urine output response is adequate and haematocrit normalises, switch to dextrose 5% normal saline and maintain at the rate of 125–150 ml/h while monitoring closely every 4 h.
    Go to context

Practice Committee of American Society for Reproductive Medicine (ASRM) Ovarian hyperstimulation syndrome Fertil Steril. 2008;90:S188-S193 2008
23

References in context

  • The prevention of OHSS includes three main strategies: identification of women at risk, using different ovulation-induction strategies before stimulation, and preventive therapy modalities during stimulation (Table 1).
    Go to context

  • Until the optimal protocol of luteal supplementation is defined, an alterative option is to freeze all oocytes and embryos (so-call ‘freeze-all’) and transfer in subsequent natural or stimulated cycles.23 The combination of agonist trigger and ‘freeze all’ gives maximum protection and may even result in better implantation.
    Go to context

J.A. Garcia-Velasco Agonist trigger: what is the best approach? Agonist trigger with vitrification of oocytes or embryos Crossref. Fertil Steril. 2012;97:527-528 2012
24

References in context

  • A systematic review and meta-analysis of the existing literature24 showed that both anti-Müllerian hormone and antral follicle count are accurate predictors of excessive response to ovarian hyperstimulation.
    Go to context

S.L. Broer, M. Dólleman, B.C. Opmeer, et al. AMH and AFC as predictors of excessive response in controlled ovarian hyperstimulation: a meta-analysis Crossref. Hum Reprod Update. 2011;17:46-54 2011
27

References in context

  • Gonadotrophins can be used for induction of ovulation in anovulatory women or ovarian stimulation for intrauterine insemination or IVF.
    Go to context

F. Olivennes Ovarian hyperstimulation syndrome prevention strategies: individualizing gonadotrophin dose Crossref. Semin Reprod Med. 2010;28:463-467 2010
28

References in context

  • Gonadotrophins can be used for induction of ovulation in anovulatory women or ovarian stimulation for intrauterine insemination or IVF.
    Go to context

A. Enskog, M. Henriksson, M. Unander, et al. Prospective study of the clinical and laboratory parameters of patients in whom ovarian hyperstimulation syndrome developed during controlled ovarian hyperstimulation for in vitro fertilization Crossref. Fertil Steril. 1999;71:808-814 1999
29

References in context

  • The basis of the classic chronic, low-dose, step-up protocol is to identify the threshold dose that is necessary to induce follicular maturation, especially in women suffering from PCOS.29 The protocol normally starts with a dose of 75 IU daily for 14 days, followed by small stepwise increases (37.5 IU or less) for a period of 7 days.
    Go to context

R. Homburg, C.M. Howles Low-dose FSH therapy for anovulatory infertility associated with polycystic ovary syndrome: rationale, results, reflections and refinements Crossref. Hum Reprod Update. 1999;5:493-499 1999
30

References in context

  • The aim of the step-down protocol30 is to rapidly achieve the FSH threshold for stimulating follicle development, and thus step-down regimens normally begin with a dose of 150 IU FSH daily followed by reduction of the dose once the initial response is established.
    Go to context

E.J. van Santbrink, B.C. Fauser Urinary follicle-stimulating hormone for normogonadotropic clomiphene-resistant anovulatory infertility: prospective, randomized comparison between low dose step-up and step-down dose regimens J Clin Endocrinol Metab. 1997;82:3597-3602 1997
31

References in context

  • The aim of the step-down protocol30 is to rapidly achieve the FSH threshold for stimulating follicle development, and thus step-down regimens normally begin with a dose of 150 IU FSH daily followed by reduction of the dose once the initial response is established.
    Go to context

Thessaloniki ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group Consensus on infertility treatment related to polycystic ovary syndrome Hum Reprod. 2008;23:462-477 2008
*32

References in context

  • A Cochrane review32 concluded that the use of antagonist compared with long GnRH agonist protocols was associated with a large reduction in OHSS, with no evidence of a difference in live-birth rates.
    Go to context

H.G. Al-Inany, M.A. Youssef, M. Aboulghar, et al. Gonadotrophin-releasing hormone antagonists for assisted reproductive technology Cochrane Database Syst Rev. 2011;5:CD001750 2011
33

References in context

  • The data, however, are inconclusive from a recent systematic review and meta-analysis,33 which investigated whether GnRH antagonist protocols reduce the risk of OHSS in women with PCOS undergoing IVF compared with the long agonist protocol.
    Go to context

J. Pundir, S.K. Sunkara, T. El-Toukhy, et al. Meta-analysis of GnRH antagonist protocols: do they reduce the risk of OHSS in PCOS? Crossref. Reprod Biomed Online. 2012;24:6-22 2012
34

References in context

  • Although the pregnancy and implantation rates of in-vitro maturation (IVM) treatment are not as high as conventional IVF treatment, immature oocyte retrieval followed by IVM is a promising potential treatment option for infertile women with PCOS, because this group of women are extremely sensitive to stimulation with exogenous gonadotrophins and is at increased risk of developing OHSS.34 It has been shown that priming with FSH or hCG before immature oocyte retrieval improved oocyte maturation and pregnancy rates.35 Therefore, IVM treatment represents an attractive alternative to cycle cancellation, coasting, or embryo cryopreservation.
    Go to context

J.Y. Huang, R.C. Chian, S.L. Tan Ovarian hyperstimulation syndrome prevention strategies: in vitro maturation Crossref. Semin Reprod Med. 2010;28:519-531 2010
35

References in context

  • Although the pregnancy and implantation rates of in-vitro maturation (IVM) treatment are not as high as conventional IVF treatment, immature oocyte retrieval followed by IVM is a promising potential treatment option for infertile women with PCOS, because this group of women are extremely sensitive to stimulation with exogenous gonadotrophins and is at increased risk of developing OHSS.34 It has been shown that priming with FSH or hCG before immature oocyte retrieval improved oocyte maturation and pregnancy rates.35 Therefore, IVM treatment represents an attractive alternative to cycle cancellation, coasting, or embryo cryopreservation.
    Go to context

J.E.J. Smitz, J.G. Thompson, R.B. Gilchrist The promise of in vitro maturation in assisted reproduction and fertility preservation Semin Reprod Med. 2011;29:24-37 2011
36

References in context

  • In women with PCOS, short-term treatment with metformin did not improve the response to stimulation but it did improve the pregnancy outcome and reduced the incidence of OHSS.36 A meta-analysis of RCTs showed that the administration of metformin significantly reduced the risk of OHSS.37 These findings were obtained from four RCTs that included 449 participants with PCOS who were scheduled for IVF cycles.
    Go to context

T. Tang, J. Glanville, N. Orsi, et al. The use of metformin for women with PCOS undergoing IVF treatment Crossref. Hum Reprod. 2006;21:1416-1425 2006
37

References in context

  • In women with PCOS, short-term treatment with metformin did not improve the response to stimulation but it did improve the pregnancy outcome and reduced the incidence of OHSS.36 A meta-analysis of RCTs showed that the administration of metformin significantly reduced the risk of OHSS.37 These findings were obtained from four RCTs that included 449 participants with PCOS who were scheduled for IVF cycles.
    Go to context

L.O. Tso, M.F. Costello, L.E. Albuquerque, et al. Metformin treatment before and during IVF or ICSI in women with polycystic ovary syndrome Cochrane Database Syst Rev. 2009;15:CD006105 2009
38

References in context

  • A recent large RCT found that metformin effectively reduces the incidence of OHSS in a high-risk population of women with PCOS who are receiving gonadotrophin for IVF.38 The action of metformin is still unknown.
    Go to context

S. Palomba, A. Falbo, L. Carrillo, et al. Metformin reduces risk of ovarian hyperstimulation syndrome in patients with polycystic ovary syndrome during gonadotrophin-stimulated in vitro fertilization cycles: a randomized, controlled trial Fertil Steril. 2011;96:1384-1390.e4 2011
39

References in context

  • Cycle cancellation and withholding of hCG is the only guaranteed method for preventing early OHSS.39 At present, it is less widely used because of the development of the more acceptable strategies such as coasting.
    Go to context

  • Luteal support with hCG is associated with a higher risk for OHSS and should be avoided.56 The use of exogenous progesterone (e.g. 50 mg progesterone in oil intramuscular, 100 mg progesterone vaginal suppositories, or 8% progesterone vaginal gel, daily) for luteal phase support rather than supplemental doses of hCG, may further reduce risks of OHSS.39 When symptoms of OHSS emerge even before administration of hCG, cycle cancellation and less aggressive stimulation in a subsequent cycle should be seriously considered.
    Go to context

R.G. Forman, R. Frydman, D. Egan, et al. Severe ovarian hyperstimulation syndrome using agonists of gonadotrophin-releasing hormone for in vitro fertilization: a European series and a proposal for prevention Fertil Steril. 1990;53:502-509 1990
40

References in context

  • Withholding further gonadotrophin stimulation and delaying hCG administration until oestradiol levels plateau or decrease significantly can reduce risks of OHSS.40 Coasting does not eliminate the risk of OHSS but may reduce the incidence and severity of the condition.
    Go to context

A. Delvigne, S. Rozenberg A qualitative systematic review of coasting, a procedure to avoid ovarian hyperstimulation syndrome in IVF patients Crossref. Hum Reprod Update. 2002;8:291-296 2002
41

References in context

  • According to a recent Cochrane review,41 no evidence suggested a benefit of using coasting to prevent OHSS compared with no coasting or other interventions.
    Go to context

A. D'Angelo, J. Brown, N.N. Amso Coasting (withholding gonadotrophins) for preventing ovarian hyperstimulation syndrome Cochrane Database Syst Rev. 2011;6:CD002811 2011
42

References in context

  • Initiating coasting depends on both oestradiol levels and numbers and size of follicles.42 It is generally accepted that coasting should be initiated when the oestradiol level is greater than 3000 pg/mL in the setting of numerous immature follicles (<16 mm) with rapidly increasing oestradiol level.43,44 Human chorionic gonadotrophin can be given when oestradiol levels drop to a ‘safe’ level (e.g. 3000 pg/mL).
    Go to context

C.D. Chen, K.H. Chao, J.H. Yang, et al. Comparison of coasting and intravenous albumin in the prevention of ovarian hyperstimulation syndrome Crossref. Fertil Steril. 2003;80:86-90 2003
43

References in context

  • Initiating coasting depends on both oestradiol levels and numbers and size of follicles.42 It is generally accepted that coasting should be initiated when the oestradiol level is greater than 3000 pg/mL in the setting of numerous immature follicles (<16 mm) with rapidly increasing oestradiol level.43,44 Human chorionic gonadotrophin can be given when oestradiol levels drop to a ‘safe’ level (e.g. 3000 pg/mL).
    Go to context

R. Abdallah, I. Kligman, O. Davis, et al. Withholding gonadotrophins until human chorionic gonadotrophin administration Crossref. Semin Reprod Med. 2010;28:486-492 2010
45

References in context

  • Prophylactic intravenous administration of 25% albumin (20–50 g) at time of oocyte retrieval has been suggested as a means of reducing risk of OHSS.
    Go to context

  • An alternative to human albumin is hydroxyethyl solution (1000 mL 6% at the time of oocyte retrieval, followed by another 500 mL 48 h later).
    Go to context

M.A. Youssef, H.G. Al-Inany, J.L. Evers, et al. Intra-venous fluids for the prevention of severe ovarian hyperstimulation syndrome Cochrane Database Syst Rev. 2011;16:CD001302 2011
46

References in context

  • Prophylactic intravenous administration of 25% albumin (20–50 g) at time of oocyte retrieval has been suggested as a means of reducing risk of OHSS.
    Go to context

  • Prophylactic intravenous administration of 25% albumin (20–50 g) at time of oocyte retrieval has been suggested as a means of reducing risk of OHSS.
    Go to context

C.A. Venetis, E.M. Kolibianakis, K.A. Toulis, et al. Intravenous albumin administration for the prevention of severe ovarian hyperstimulation syndrome: a systematic review and metaanalysis Fertil Steril. 2011;95:188-196 2011
47

References in context

  • The incidence of OHSS was not reduced in the high-risk population even with lower dose of urinary hCG.47 Owing to the lack of concrete evidence, it is believed that the dose of hCG should be individualised in the same way as the starting dose of gonadotrophins.
    Go to context

I. Tsoumpou, J. Muglu, T.A. Gelbaya, et al. Symposium: update on prediction and management of OHSS. Optimal dose of HCG for final oocyte maturation in IVF cycles: absence of evidence? Crossref. Reprod Biomed Online. 2009;19:52-58 2009
48

References in context

  • Agonist triggering offers the possibility to individually tailor the luteal phase support according to the ovarian response to stimulation.48 Most recent studies have used single doses of the following types of GnRH agonist: either triptorelin 0.2 mg,49 buserelin 0.5 mg,50 or leuprolide acetate 1.5 mg.51 Most studies support supplementation with luteinising hormone activity in addition to standard luteal phase support with oestradiol and progesterone.
    Go to context

P. Humaidan Agonist trigger: what is the best approach? Agonist trigger and low dose hCG Crossref. Fertil Steril. 2012;97:529-530 2012
49

References in context

  • Agonist triggering offers the possibility to individually tailor the luteal phase support according to the ovarian response to stimulation.48 Most recent studies have used single doses of the following types of GnRH agonist: either triptorelin 0.2 mg,49 buserelin 0.5 mg,50 or leuprolide acetate 1.5 mg.51 Most studies support supplementation with luteinising hormone activity in addition to standard luteal phase support with oestradiol and progesterone.
    Go to context

  • Agonist triggering offers the possibility to individually tailor the luteal phase support according to the ovarian response to stimulation.48 Most recent studies have used single doses of the following types of GnRH agonist: either triptorelin 0.2 mg,49 buserelin 0.5 mg,50 or leuprolide acetate 1.5 mg.51 Most studies support supplementation with luteinising hormone activity in addition to standard luteal phase support with oestradiol and progesterone.
    Go to context

E.G. Papanikolaou, W. Verpoest, H. Fatemi, et al. A novel method of luteal supplementation with recombinant luteinizing hormone when a gonadotrophin-releasing hormone agonist is used instead of human chorionic gonadotrophin for ovulation triggering: a randomized prospective proof of concept study Crossref. Fertil Steril. 2011;95:1174-1177 2011
50

References in context

  • Agonist triggering offers the possibility to individually tailor the luteal phase support according to the ovarian response to stimulation.48 Most recent studies have used single doses of the following types of GnRH agonist: either triptorelin 0.2 mg,49 buserelin 0.5 mg,50 or leuprolide acetate 1.5 mg.51 Most studies support supplementation with luteinising hormone activity in addition to standard luteal phase support with oestradiol and progesterone.
    Go to context

P. Humaidan, H.E. Bredkjaer, L. Bungum, et al. GnRH agonist (buserelin) or hCG for ovulation induction in GnRH antagonist IVF/ICSI cycles: a prospective randomized study Crossref. Hum Reprod. 2005;20:1213-1220 2005
51

References in context

  • Agonist triggering offers the possibility to individually tailor the luteal phase support according to the ovarian response to stimulation.48 Most recent studies have used single doses of the following types of GnRH agonist: either triptorelin 0.2 mg,49 buserelin 0.5 mg,50 or leuprolide acetate 1.5 mg.51 Most studies support supplementation with luteinising hormone activity in addition to standard luteal phase support with oestradiol and progesterone.
    Go to context

  • Agonist triggering offers the possibility to individually tailor the luteal phase support according to the ovarian response to stimulation.48 Most recent studies have used single doses of the following types of GnRH agonist: either triptorelin 0.2 mg,49 buserelin 0.5 mg,50 or leuprolide acetate 1.5 mg.51 Most studies support supplementation with luteinising hormone activity in addition to standard luteal phase support with oestradiol and progesterone.
    Go to context

J.C. Castillo, M. Dolz, E. Bienvenido, et al. Cycles triggered with GnRH agonist: exploring low-dose HCG for luteal support Crossref. Reprod Biomed Online. 2010;20:175-181 2010
*52

References in context

  • Gonadotrophin-releasing hormone agonist triggering is now a valid alternative to hCG triggering.
    Go to context

P. Humaidan, H.E. Bredkjaer, L.G. Westergaard, et al. 1500 IU human chorionic gonadotrophin administered at oocyte retrieval rescues the luteal phase when gonadotrophin-releasing hormone agonist is used for ovulation induction: a prospective, randomized, controlled study Crossref. Fertil Steril. 2010;93:847-854 2010
*53

References in context

  • A recent meta-analysis showed that the modified luteal support has had a significant positive effect on the reproductive outcome after GnRH agonist triggering without an increase in the OHSS rate.53 Nevertheless, the most optimal luteal phase support still has to be explored.
    Go to context

P. Humaidan, S. Kol, E. Papanikolaou GnRH agonist for triggering of final oocyte maturation: time for a change of practice? Crossref. Hum Reprod Update. 2011;17:510-524 2011
56

References in context

  • Luteal support with hCG is associated with a higher risk for OHSS and should be avoided.56 The use of exogenous progesterone (e.g. 50 mg progesterone in oil intramuscular, 100 mg progesterone vaginal suppositories, or 8% progesterone vaginal gel, daily) for luteal phase support rather than supplemental doses of hCG, may further reduce risks of OHSS.39 When symptoms of OHSS emerge even before administration of hCG, cycle cancellation and less aggressive stimulation in a subsequent cycle should be seriously considered.
    Go to context

M. van der Linden, K. Buckingham, C. Farquhar, et al. Luteal phase support for assisted reproduction cycles Cochrane Database Syst Rev. 2011;5:CD009154 2011
57

References in context

  • In a recently updated Cochrane review, however, there is insufficient evidence to support routine cryopreservation.57 The reviewers concluded that these results have to be interpreted with caution because of the small number of women in the individual studies.
    Go to context

A. D'Angelo, N. Amso Embryo freezing for preventing ovarian hyperstimulation syndrome Cochrane Database Syst Rev. 2007;18:CD002806 2007
60

References in context

  • Administration of a dopamine or dopamine receptor 2 agonist, inactivates VEGFR-2 and prevents the increase in vascular permeability.60 Cabergoline 0.5 mg tablet daily starting on the day of hCG injection and continue for 8 days have been shown to reduce the risk of severe OHSS.
    Go to context

S. Basu, J.A. Nagy, S. Pal, et al. The neurotransmitter dopamine inhibits angiogenesis induced by vascular permeability factor/vascular endothelial growth factor Crossref. Nat Med. 2001;7:569-574 2001
61

References in context

  • The increase vascular permeability seen in OHSS is primarily caused by ovarian secretion of vascular endothelial growth factor, which activates its receptor (VEGFR-2).
    Go to context

M.A. Youssef, M. van Wely, M.A. Hassan, et al. Can dopamine agonists reduce the incidence and severity of OHSS in IVF/ICSI treatment cycles? A systematic review and meta-analysis Crossref. Hum Reprod Update. 2010;16:459-466 2010
62

References in context

  • Low-dose aspirin therapy for prevention of OHSS is based on the theory that superovulation treatment may induce platelet hyperstimulation, which is associated with OHSS, and that aspirin therapy may inhibit this effect.
    Go to context

A. Varnagy, J. Bodis, Z. Manfai, et al. Low-dose aspirin therapy to prevent ovarian hyperstimulation syndrome Fertil Steril. 2009;93:2281-2284 2009

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