Human Reproduction, Vol. 14, No. 9, 2183-2185,
September 1999
© 1999 European Society of Human Reproduction and Embryology
Debate |
Severe OHSS
Patients should be allowed to weigh the morbidity of OHSS against the benefits of parenthood
Division of Reproductive Medicine, University Department of Obstetrics and Gynaecology, St Michael's Hospital, Southwell treet, Bristol, BS2 8EG, UK
Severe ovarian hyperstimulation syndrome (OHSS) is a potentially life threatening complication of supraphysiological ovarian stimulation. Evidence of an increase in the annual incidence of OHSS and a disproportionate increase in the proportion of severe cases in Israel in the decade beginning January 1987 has been found (Abramov et al., 1999
). These authors relate this to an increase both in the number of in-vitro fertilization (IVF) cycles performed in Israel over the study period and in the risk of severe OHSS per cycle of IVF. The prevention of OHSS remains a difficult clinical and scientific problem, with no available measure guaranteed to have complete efficacy. In this article, we discuss the difficulties involved in the prevention of OHSS and the need for a wider dissemination of information regarding available preventative measures. It is also important to consider the problem of OHSS in perspective and ensure that adequate counselling remains a key part of the process of informed decision-making in couples undergoing assisted conception treatment.
There are three main factors inhibiting the development and evaluation of measures directed at preventing OHSS: an imperfect understanding of the pathogenesis, a lack of criteria that can reliably predict the occurrence of OHSS and the relatively small number of cases seen by a single unit. Recent advances in determining the role of the immune system and cytokines in the pathogenesis of OHSS may ultimately assist in the development of more effective preventative measures. However, at present there is no specific immune-based intervention that can be used in clinical practice to prevent OHSS (Mathur et al., 1997a).
The difficulty of identifying accurately a high-risk group that can be targeted for specific preventative measures is a major problem in trying to prevent OHSS. There is considerable discrepancy in the literature between studies using identical criteria to predict the risk of OHSS (Asch et al., 1991; Morris et al., 1995). A significant proportion of cases of severe OHSS may occur in cycles where no risk factors are identified in terms of patient or cycle characteristics (Delvigne et al., 1997). The explanation for this may lie in the probable occurrence of OHSS in two forms, distinguished by time of onset (Dahl Lyons et al., 1994). Early OHSS can to an extent be predicted by pre-ovulatory indices of ovarian response in time to institute preventative measures such as cancellation, coasting or i.v. albumin. Late OHSS does not relate strongly to pre-ovulatory ovarian response, making it difficult to identify cycles where it is likely to occur (Mathur et al., 1997b).
The lack of accurate predictive parameters limits the value of preventative measures, such as cryopreservation of all embryos with delayed transfer, which cannot be generalised to all cycles. However, universally applicable measures designed to reduce exposure to human chorionic gonadotrophin (HCG) in the luteal phase may help to ameliorate or prevent late OHSS. The use of progesterone rather than HCG for luteal support is one such measure (Soliman et al., 1994). Minimizing the incidence of triplet and higher-order multiple gestations may be another method of reducing HCG exposure and, possibly, the risk of late OHSS. In the original description, late OHSS was only observed in cycles with multiple gestations (Dahl Lyons et al., 1994). Although we have observed late OHSS in cycles with singleton as well as multiple gestations, late OHSS is more likely in the presence of multiple as opposed to singleton gestation (Mathur et al., 1995) and there is a trend to increasing severity of OHSS with increasing numbers of gestation sacs. We are tempted to postulate that a restriction in the number of embryos transferred and a consequent reduction in the proportion of triplet and higher-order multiple gestations would be associated with a lower incidence of severe late OHSS.
Given a typical incidence of severe OHSS of <1%, even large units are likely to encounter only a relatively small number of cases, presenting a problem in evaluating the effectiveness of existing measures. Six years since the use of albumin administered i.v. around the time of oocyte retrieval was first reported as a method for preventing OHSS (Asch et al., 1993), its role remains unclear. The number of patients in pooled randomized trials in the literature lacks the statistical power to establish the efficacy or otherwise of this treatment (Orvieto and Ben-Rafael, 1998). Concern has recently been expressed about increased mortality associated with albumin use in critically ill patients (Cochrane Injuries Group Albumin Reviewers, 1998), but the relevance of this to the situation where it is used prophylactically with the aim of preventing severe OHSS is unclear. Delaying HCG administration in cycles with an `excessive' ovarian response till the response settles to `safe' levels has been proposed as a method of preventing OHSS, but has only been evaluated in small numbers of patients and criteria for coasting have varied considerably between centres (Benadiva et al., 1997; Lee et al., 1998; Tortoriello et al., 1998). It is likely that these treatments can only be evaluated adequately by trials involving large numbers of patients in multiple centres.
Perhaps as a result of the lack of validation of existing measures, the preventative management of OHSS in clinical practice varies between treatment clinics and countries. As part of a classroom on the FertiNet website in March 1999 we initiated an ongoing survey of the management of OHSS (http://www.repromed.net/ohss/). Within the first 2 months we received 42 responses from 21 countries. The prevalence of individual preventative measures broadly matched the strength of the evidence supporting their efficacy. Given the uncertainty of benefit and safety of prophylactic albumin, only 11 respondents (26.2%) used this treatment in `high risk' cases. Recent evidence in favour of coasting is reflected in 28 respondents (66.7%) employing this strategy. A similar number of respondents (26 or 62.0%) are using cryopreservation of all embryos with delayed transfer. In all, 36 respondents (85.7%) used progesterone luteal support as a routine in all cases, while four respondents had specific criteria for the use of progesterone and two used it only rarely. As more responses are received the database will expand to identify areas of consensus and disagreement to help focus future research. Dissemination of information regarding the effectiveness and uptake of existing preventative measures, such as progesterone luteal support, should accompany research designed to develop and evaluate newer measures.
Although the incidence of significant long-term morbidity following severe OHSS is unclear, it is reassuring in that there was not a single reported fatality due to OHSS in the 73 492 cycles studied by Abramov et al. (1999). This compares favourably with operative mortality and even maternal mortality rates in developed countries and helps put the problem of OHSS in perspective. The desire of some couples for children is strong and leads them to accept a modicum of risk involved in treatment to overcome their infertility. However, while the absence of OHSS-related mortality in the above series is reassuring, severe OHSS remains a serious iatrogenic complication of a treatment that is never life-saving, thus we should endeavour to prevent its occurrence. Patients need to be counselled about the risk of developing OHSS and its consequences, but in the end must be free to make an informed decision regarding the most effective treatment for their problems. Certainly the risk of OHSS must not be used as an argument to deny funds or restrict access to assisted conception programmes which have the potential to alleviate the misery of childlessness.
Notes
1 To whom correspondence should be addressed 
This debate was previously published on Webtrack 73, 16 June 1999
References
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Asch, R.H., Li, H., Balmaceda, J.P. et al. (1991) Severe ovarian hyperstimulation syndrome in assisted reproductive technology: definition of high risk groups. Hum. Reprod., 6, 1395–1399.
Asch, R.H., Ivery, G., Goldsman, M. et al. (1993) The use of intravenous albumin in patients at high risk for ovarian hyperstimulation syndrome. Hum. Reprod., 7, 1015–1020.
Benadiva, C.A., Davis, O., Kligman, I. et al. (1997) Withholding gonadotrophin administration is an effective alternative for the prevention of severe ovarian hyperstimulation syndrome. Fertil. Steril., 67, 224–227.
Cochrane Injuries Group Albumin Reviewers (1998) Human albumin administration in critically ill patients: systematic review of randomised controlled trials. Br. Med. J., 317, 235–240
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