Hum. Reprod. Advance Access originally published online on November 26, 2004
Human Reproduction 2005 20(2):320-322; doi:10.1093/humrep/deh613
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Can we eliminate severe ovarian hyperstimulation syndrome?
Department of Obstetrics and Gynecology, Rabin Medical Center, Petah Tiqva 49 100 and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
Email: orvieto{at}clalit.org.il
 |
Abstract |
|---|
 Top Abstract IntroductionElimination of OHSSReferences |
|---|
The desire of some couples for children is so strong that they are willing to accept a modicum of risk to treat their infertility. Ideally, assisted reproduction technology practitioners seek a balance between optimum ovarian stimulation and successful treatment outcome with minimal rate of severe ovarian hyperstimulation syndrome (OHSS) or multiple pregnancies. However, despite many years of clinical experience, there are no precise methods to completely prevent severe OHSS, except by withholding the ovulation-inducing trigger of hCG. Individualization of treatment according to the specific risk factor and the specific response in the current cycle with the option of freezing of all embryos, or replacement of only a single embryo, has the potential of reducing the risk and the severity of the syndrome in susceptible cases. We offer a triage aimed at eliminating the occurrence of severe ovarian hyperstimulation syndrome on the basis of several clinical observations, including the role of GnRH antagonist in controlled ovarian stimulation protocols, the option of freezing of all embryos, or replacement of only a single embryo in the blastocyst stage.
Key words: controlled ovarian stimulation/ovarian hyperstimulation syndrome/prevention
|
Introduction |
|---|
|
TopAbstractIntroductionElimination of OHSSReferences |
|---|
Ovarian hyperstimulation syndrome (OHSS) is an iatrogenic complication of ovulation induction. Its cardinal features are marked ovarian enlargement and acute third-space fluid sequestration. The fluid shift from the intra- to the extravascular spaces in response to the increase in capillary permeability contributes most to the morbidity associated with OHSS (Navot et al., 1996
).
The syndrome almost always presents either 3–7 days after hCG administration in susceptible patients (early onset) or during early pregnancy, 12–17 days after hCG administration (late onset). Early OHSS can to some extent be predicted by pre-ovulatory indices of ovarian response, in time to institute preventive measures such as cancellation (Hancock et al., 1970). Late OHSS does not relate strongly to pre-ovulatory ovarian response, making it difficult for clinicians to identify the cycles in which it is likely to occur (Mathur et al., 1997). In the original description of OHSS, the late form was observed only in cycles with multiple gestations (Lyons et al., 1994), with a trend toward an increase in the severity of disease with an increase in the number of gestational sacs (Mathur et al., 1995).
Several articles have reviewed the epidemiological, hormonal and ultrasonographic characteristics of patients susceptible to OHSS (Blankstein et al., 1987; Asch et al., 1991; Navot et al., 1992, 1996; Morris et al., 1995; Zalel et al., 1995; Levy et al., 1996; Delvigne and Rozenberg, 2002). Despite the many years of clinical experience, however, the pathophysiology of OHSS remains poorly understood, and there is no reliable test to predict which patients will develop severe OHSS (American Society for Reproductive Medicine Practice Committee, 2004). When all the accepted predictive variables were combined, the prevalence of severe OHSS in the ostensibly high-risk patients was only 
20% (Delvigne and Rozenberg, 2002; Orvieto and Ben-Rafael, 1998)—an extremely low value for reliable prediction.
With the introduction in 1987 of GnRH agonists to the controlled ovarian stimulation (COS) protocols, clinicians initiated treatment with higher doses of gonadotrophins for retrieval of a higher number of mature oocytes. These protocols came into widespread use because of their higher conception and lower cancellation rates (Fleming et al., 1985). Unfortunately, they were also associated with an increased occurrence of OHSS (Forman et al., 1990).
Alternatively, GnRH agonist can induce a sustained release of LH and FSH from the pituitary (‘flare effect’), which effectively triggers oocyte maturation and ovulation, making it a potential alternative to hCG. However, the use of this approach was limited by its inapplicability in GnRH agonist-induced pituitary down-regulation-based protocols. Recently, some authors have suggested that replacing hCG with GnRH agonist can reduce the occurrence of OHSS (Balasch et al., 1994, reviewed by Kol, 2004).
Morris et al. (1995) studied assisted reproduction cycles by oocyte donor and classical IVF patients, in which E2 (>4000 pg/ml) or oocyte number (>25) or both were elevated. While there were no cases of severe OHSS in the oocyte donor group, six cases of severe OHSS were observed in the classical IVF group. The calculated relative risk of OHSS with pregnancy was 12-fold higher. The authors concluded that the risk of OHSS even at high levels of stimulation is lower than previously believed and that donors have a very low risk of OHSS, probably because of the absence of pregnancy. As such, cryopreservation of all oocytes in IVF cycles is a reasonable alternative. Their findings were supported by Mathur et al. (1995) who observed that OHSS may be more likely if multiple pregnancy occurs following assisted conception. However, other studies showed that when there is serious risk of severe OHSS, cryopreservation of all resulting embryos may prevent pregnancy-associated late OHSS, but not early-onset OHSS, which is precipitated with the trigger hCG dose (Lyons et al., 1994; Queenan et al., 1997).
The best means of prevention is individualization. Based on the aforementioned clinical observations and our personal experience, the occurrence of severe OHSS has been eliminated by strict adherence to the following triage (Figure 1).
|
|
Elimination of OHSS |
|---|
|
TopAbstractIntroductionElimination of OHSSReferences |
|---|
Severe OHSS can be almost totally prevented by withholding the ovulation-inducing trigger of hCG in patients at high risk, or by replacing hCG with GnRH agonist to trigger ovulation (Kol, 2004
). We therefore believe that today, in normal and high-responder patients undergoing their first IVF attempt, it would be prudent to perform COS with a GnRH antagonist in combination with GnRH agonist to trigger ovulation. In patients in whom <20 oocytes are retrieved, and in low responders (who are expected to recruit <10 follicles) or patients 
40 years old, the COS protocol should be individually tailored. If the combined GnRH antagonist/agonist or the tailored COS protocols yield 20 oocytes, or 10 embryos develop, the patient should be followed for 5 days after oocyte retrieval for signs of early OHSS (ultrasonographic signs of ascites, Hct levels for the degree of haemoconcentration). If signs develop, embryo transfer should be withheld and all resulting embryos cryopreserved. This will limit early OHSS, if it appears, to a milder and shorter form. If it does not appear, the transfer of one blastocyst will decrease the risk of multiple pregnancy to almost zero, thereby eliminating the risk of late OHSS. In patients with <20 oocytes, the number of embryos transferred and the time of transfer should adhere to the standard practice of the specific IVF unit.
|
References |
|---|
|
TopAbstractIntroductionElimination of OHSSReferences |
|---|
Asch RH, Li H, Balmaceda JP, Weckstein LN and Stone SC (1991) Severe ovarian hyperstimulation syndrome in assisted reproductive technology: definition of high risk groups. Hum Reprod 6, 1395–1399.
American Society for Reproductive Medicine Practice Committee (2004) Ovarian hyperstimulation syndrome. Fertil Steril 82, S81–S86.
Balasch J, Tur R, Creus M, Buxaderas R, Fabregues F, Ballesca JL, Barri PN and Vanrell JA (1994) Triggering of ovulation by gonadotropin releasing hormone agonist in gonadotropin-stimulated cycles for prevention of ovarian hyperstimulation syndrome and multiple pregnancy. Gynecol Endocrinol 8, 7–12.[Web of Science][Medline]
Blankstein J, Shalev J, Saadon T, Kukia EE, Rabinovici J, Pariente C, Lunenfeld B, Serr DM and Mashiach S (1987) Ovarian hyperstimulation syndrome: prediction by number and size of preovulatory ovarian follicles. Fertil Steril 47, 597–602.[Web of Science][Medline]
Delvigne A and Rozenberg S (2002) Epidemiology and prevention of ovarian hyperstimulation syndrome (OHSS): a review. Hum Reprod Update 8, 559–577.
Fleming R, Haxton MJ, Hamilton MPR, McCune GS, Black WP, MaNaughton MC and Coutts Jr (1985) Successful treatment of infertile women with oligomenorrhoea using a combination of an LHRH agonist and exogenous gonadotrophins. Br J Obstet Gynaecol 92, 369–373.[Web of Science][Medline]
Forman RG, Frydman R, Egan D, Ross C and Barlow DH (1990) Severe hyperstimulation syndrome using agonists of gonadotropin-releasing hormone for in vitro fertilization: a European series and a proposal for prevention. Fertil Steril 53, 502–509.[Web of Science][Medline]
Hancock KW, Stitch SR, Oakey R, Scott JS, Levell MJ and Ellis FR (1970) Ovulation induction. Problems of prediction of response to gonadotrophin. Lancet 2, 482–485.[CrossRef][Web of Science][Medline]
Kol S (2004) Luteolysis induced by a gonadotropin-releasing hormone agonist is the key to prevention of ovarian hyperstimulation syndrome. Fertil Steril 81, 1–5.[Web of Science][Medline]
Levy T, Orvieto R, Homburg R, Dekel A, Peleg D and Ben-Rafael Z (1996) Severe ovarian hyperstimulation syndrome despite low plasma estrogen levels in a hypogonadotropic hypogonadal patient. Hum Reprod 11, 1177–1179.
Lyons CA, Wheeler CA, Frishman GN, Hackett RJ, Seifer DB and Hanning RVJ (1994) Early and late presentation of the ovarian hyperstimulation syndrome: two distinct entities with different risk factors. Hum Reprod 9, 792–799.
Mathur RS, Joels LA, Jenkins JM, Hunt LP and Jenkins JM (1995) Ovarian hyperstimulation syndrome may be more likely if multiple pregnancy follows assisted conception. Acta Genet Med Gemellol 44, 233–235.[Medline]
Mathur RS, Akande AV, Keay SD et al. (1997) Late onset OHSS after ovarian stimulation is poorly predicted by peak oestradiol concentration and number of oocytes collected. Hum Reprod 12(Abstr Book 1), R-229.
Morris RS, Paulson RJ, Sauer MV and Lobo RA (1995) Predictive value of serum oestradiol concentrations and oocyte number in severe ovarian hyperstimulation syndrome. Hum Reprod 10, 811–814.
Navot D, Bergh PA and Laufer N (1992) Ovarian hyperstimulation syndrome in novel reproductive technologies: prevention and treatment. Fertil Steril 58, 249–261.[Web of Science][Medline]
Navot D, Bergh PA and Laufer N (1996) The ovarian hyperstimulation syndrome. In Adashi E, Rock JA, and Rosenwaks Z (eds) Reproductive Endocrinology, Surgery, and Technology. Lippincott–Raven Publishers, Philadelphia, pp. 2215–2232.
Orvieto R and Ben-Rafael Z (1998) Role of intravenous albumin in the prevention of severe ovarian hyperstimulation syndrome. Hum Reprod 13, 3306–3309.
Queenan JT, Veeck LL, Toner JP, Oehninger S and Muasher SJ (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. Hum Reprod 12, 1573–1576.
Zalel Y, Orvieto R, Ben-Rafael Z, Homburg R, Fisher O and Insler V (1995) Recurrent spontaneous ovarian hyperstimulation syndrome associated with polycystic ovary syndrome. Gynecol Endocrinol 9, 313–315.[Web of Science][Medline]
Submitted on June 24, 2004; resubmitted on August 31, 2004; accepted on October 21, 2004.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  P. Humaidan, E.G. Papanikolaou, and B.C. Tarlatzis GnRHa to trigger final oocyte maturation: a time to reconsider Hum. Reprod., October 1, 2009; 24(10): 2389 - 2394. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. B. Stanek, S. M. Borman, T. A. Molskness, J. M. Larson, R. L. Stouffer, and P. E. Patton Insulin and Insulin-Like Growth Factor Stimulation of Vascular Endothelial Growth Factor Production by Luteinized Granulosa Cells: Comparison between Polycystic Ovarian Syndrome (PCOS) and Non-PCOS Women J. Clin. Endocrinol. Metab., July 1, 2007; 92(7): 2726 - 2733. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Groten, H.M. Fraser, W.C. Duncan, R. Konrad, R. Kreienberg, and C. Wulff Cell junctional proteins in the human corpus luteum: changes during the normal cycle and after HCG treatment Hum. Reprod., December 1, 2006; 21(12): 3096 - 3102. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 U.-H. Stenman, A. Tiitinen, H. Alfthan, and L. Valmu The classification, functions and clinical use of different isoforms of HCG Hum. Reprod. Update, November 1, 2006; 12(6): 769 - 784. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Pau, I. Alonso-Muriel, R. Gomez, E. Novella, A. Ruiz, J. A. Garcia-Velasco, C. Simon, and A. Pellicer Plasma levels of soluble vascular endothelial growth factor receptor-1 may determine the onset of early and late ovarian hyperstimulation syndrome Hum. Reprod., June 1, 2006; 21(6): 1453 - 1460. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Griesinger, K. Diedrich, P. Devroey, and E.M. Kolibianakis Reply: Agonist trigger in the context of OHSS prevention: primum non nocere Hum. Reprod. Update, May 1, 2006; 12(3): 328 - 329. [Full Text] [PDF]
|
|
|
|
|
|
G. Griesinger, K. Diedrich, P. Devroey, and E.M. Kolibianakis GnRH agonist for triggering final oocyte maturation in the GnRH antagonist ovarian hyperstimulation protocol: a systematic review and meta-analysis Hum. Reprod. Update, March 1, 2006; 12(2): 159 - 168. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Buckett, R.-C. Chian, and S. L. Tan Can we eliminate severe ovarian hyperstimulation syndrome? Not completely Hum. Reprod., August 1, 2005; 20(8): 2367 - 2367. [Full Text] [PDF]
|
|
|
|
|
|
M. Manno Can we eliminate severe ovarian hyperstimulation syndrome? Comment I Hum. Reprod., August 1, 2005; 20(8): 2368 - 2369. [Full Text] [PDF]
|
|
|
|
|
|
D. De Neubourg and J. Gerris Can we eliminate severe ovarian hyperstimulation syndrome? Comment 2 Hum. Reprod., August 1, 2005; 20(8): 2369 - 2369. [Full Text] [PDF]
|
|
|
|
|
|
R. Orvieto Reply: Can we eliminate severe ovarian hyperstimulation syndrome? Hum. Reprod., August 1, 2005; 20(8): 2367 - 2368. [Full Text] [PDF]
|
|
|
|
|
|
R. Orvieto Replies: Can we eliminate severe ovarian hyperstimulation syndrome. Comments 1 and 2 Hum. Reprod., August 1, 2005; 20(8): 2369 - 2370. [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||