Department of Obstetrics and Gynecology, Hebrew University Hadassah Medical Center, Ein-Kerem, Jerusalem 12000, Israel
Induction of ovulation by gonadotrophins is one of the major developments in the treatment of infertility in the second half of the 20th century. Today, it is the treatment of choice for >40% of infertile women suffering from ovulatory failure. In addition, extracorporeal fertilization techniques, primarily in-vitro fertilization (IVF) and embryo transfer are used for mechanical problems, male factor, and unexplained infertility, and are practised widely in almost every country in the world today.
Successful induction of ovulation should ideally attain as many follicles and oocytes as possible to obtain the maximal number of embryos in a single treatment cycle. This goal is achieved by using regimens employing gonadotrophin-releasing hormone (GnRH) analogues and high dose gonadotrophins. Unfortunately, these regimens are associated with a serious and potentially life-threatening medical complication, i.e. ovarian hyperstimulation syndrome (OHSS). This syndrome is expressed by a variety of clinical symptoms and signs, the underlying mechanism for which is capillary hyperpermeability mediated by ovarian-derived vasoactive substances. Severe cases present with a clinical picture of systemic capillary leakage, including massive ascites, pleural and pericardial effusions, reduced effective blood volume, oliguria, haemoconcentration, thromboembolic phenomena and, occasionally, death (Schenker and Weinstein, 1978).
The exact incidence of severe OHSS in the world has not yet been determined, since most of the data on this subject derive from relatively small series. Available data, however, suggest an incidence of 0.21.0% of all assisted conception cycles (Smitz et al., 1990; Asch et al., 1991
; Brinsden et al., 1995
; Roest et al., 1996
).
In order to clarify this point, we conducted a multicentric study including 16 out of 19 tertiary medical centres in (Abramov et al., 1998). In this study, we reviewed medical records of all patients who were hospitalized for severe OHSS at these centres between January 1987 and December 1996. Cases of severe OHSS were selected according to the revised criteria (Golan et al., 1989
; Navot et al., 1992
). These include massive ascites or hydrothorax in conjunction with prominent dyspnoea, haemodynamic instability, oliguria, anasarca, liver dysfunction, adult respiratory distress syndrome (ARDS), acute renal failure, or thromboembolic phenomena.
During the period of this study, a total of 73 492 IVF cycles were performed, 2902 patients were admitted for moderate OHSS, and 209 for severe OHSS. Among the latter, 163 patients (78%) were undergoing IVF, while the rest received conventional ovulation induction treatments. Most patients (94%) with severe OHSS undergoing IVF received ovulation induction by the long protocol using pituitary suppression with GnRH analaogues, followed by exogenous gonadotrophins; 78% with an combination of folicle stimulating hormone/luteinizing hormone (FSH/LH), and 22% with pure FSH. Of the patients 13% received albumin as a preventive measure for OHSS following oocyte retrieval.
Table I shows the main signs and symptoms recorded in the study patients. Most patients presented with ascites (99%), dyspnoea (92%), haemoconcentration (95%), and gastrointestinal disturbances (54%). Oliguria was reported in 62 patients (30%), whereas massive pleural effusion appeared in 19%. Peripheral oedema occurred in 13% and thromboembolism in 2%. Five more patients (2%) had ARDS and three (1%) exhibited acute renal failure. Of the patients, 99% required therapeutic abdominal or thoracic paracentesis for alleviation of dyspnoea or oliguria.
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The first trend may be explained by the technical improvement in laboratory facilities and the advent of micromanipulation techniques which lead to higher conception rates and thus higher popularity of assisted reproductive methods. This trend may also be attributed to the multitude of severe male infertility couples who until recently would not have been candidates for any fertility treatment but today can be managed successfully by these methods.
Nevertheless, the above explanations cannot fully justify the substantial rise in severe OHSS rates described in this report. No doubt the over-utilization of high-dose gonadotrophin protocols by assisted reproductive units today carries some responsibility for this phenomenon. These units seem to have become more competitive during the last few years, with oocyte and embryo numbers being considered as main criteria for their success. With recent refinements in embryo and oocyte cryopreservation, facilitating repeat embryo transfers, these numbers have become even more important in terms of overall pregnancy rates. Expansion of oocyte donation programmes where high-dose gonadotrophin regimens play a key-role in achieving maximal numbers of oocytes for donation may have also contributed their part to this trend.
Another possible explanation for this phenomenon is the increasing prevalence of ovulation induction protocols which practise pituitary suppression with a GnRH analogue. These protocols have gained popularity owing to their higher conception and lower cancellation rates (Fleming et al., 1988). However, these protocols have been associated with a higher risk of OHSS (Forman et al., 1990
). Of the patients with severe OHSS described in our report, 94% were treated with one of these protocols.
Since the incidence of severe OHSS in Israel as presented in this study is lower than that reported worldwide (see above), this phenomenon may be even more serious in other parts of the world. In fact, over-utilization of ovulation induction medication by IVF units worldwide has been suggested previously (Edwards et al., 1996, 1997
) with respect not only to OHSS but also to other undesired consequences, such as multiple pregnancies and increased costs.
Hence, we should ask ourselves how far we are willing to go in treating infertility, and where we should draw the line so that life is not endangered. Various prophylactic methods, e.g. i.v. albumin (Orvieto and Ben-Rafael, 1998) or coasting (Lee et al., 1998
), do not appear to reliably prevent OHSS in all cases. Thus, revision of the eligibility criteria for extracorporeal fertilization treatments as well as serious reconsideration of the currently used ovulation induction regimens, especially those with GnRH analogue pituitary suppression, are strongly recommended.
Notes
1 To whom correspondence should be addressed
This debate was previously published on Webtrack 71, June 4, 1999
References
Abramov, Y., Elchalal, U. and Schenker, J.G. (1998) Febrile morbidity in severe and critical ovarian hyperstimulation syndrome: a multicentre study. Hum. Reprod., 13, 31283131.[Abstract]
Asch, R.H., Li, H.P., Balamceda, J.P. et al. (1991) Severe ovarian hyperstimulation syndrome in assisted reproductive technology: definition of high risk groups. Hum. Reprod., 6, 13959.[Abstract]
Brinsden, P.R., Wada, I., Tan, S.L. et al. (1995) Diagnosis, prevention and management of ovarian hyperstimulation syndrome. Br. J. Obstet. Gynaecol., 102, 767772.[ISI][Medline]
Edwards, R.G., Lobo, R.A. and Bouchard, P. (1996) Time to revolutionize ovarian stimulation. Hum. Reprod., 11, 917919.[ISI][Medline]
Edwards, R.G., Lobo, R.A. and Bouchard, P. (1997) Why delay the obvious need for milder forms of ovarian stimulation? Hum. Reprod., 12, 399401.[ISI][Medline]
Fleming, R., Haxton, M.J., Hamilton, M.P.R. et al. (1988) Combined gonadotropin-releasing hormone analog and exogenous gonadotropins for ovulation induction in infertile women: Efficacy related to ovarian function assessment. Am. J. Obstet. Gynecol., 159, 376381.[ISI][Medline]
Forman, R.G., Frydman, R., Egan, D. et al. (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, 502509.[ISI][Medline]
Golan, A., Ron-El, R., Herman, A. et al. (1989) Ovarian hyperstimulation syndrome: an update review. Obstet. Gynecol. Surv., 44, 430440.[Medline]
Lee, C., Tummon, I., Martin, J. et al. (1998) Does witholding gonadotrophin administration prevent severe ovarian hyperstimulation syndrome? Hum. Reprod., 13, 11571158.[Abstract]
Navot, D., Bergh, P.A. and Laufer, N. (1992) Ovarian hyperstimulation syndrome in novel reproductive technologies: prevention and treatment. Fertil. Steril., 58, 249261.[ISI][Medline]
Orvieto, R. and Ben-Rafael, Z. (1998) Role of intravenous albumin in the prevention of severe ovarian hyperstimulation syndrome. Hum. Reprod., 13, 33063309.
Roest, J., Mous, H.V., Zeilmaker, G.H. et al. (1996) The incidence of major clinical complications in a Dutch transport IVF programme. Hum. Reprod. Update, 2, 345353.
Schenker, J.G. and Weinstein, D. (1978) Ovarian hyperstimulation syndrome. Fertil. Steril., 30, 255268.[ISI][Medline]
Smitz, J., Camus, M., Devroey, P. et al. (1990) Incidence of severe ovarian hyperstimulation syndrome after GnRH agonist/HMG superovulation for in-vitro fertilization. Hum. Reprod., 5, 933937.[Abstract]