British Fertility Society Policy and Practice Committee: prevention of ovarian hyperstimulation syndrome.

Human Fertility, 2014; 17(4): 257–268 © 2014 The British Fertility Society ISSN 1464-7273 print/ISSN 1742-8149 online DOI: 10.3109/14647273.2014.961745

POLICY AND PRACTICE

British Fertility Society Policy and Practice Committee: Prevention of Ovarian Hyperstimulation Syndrome R. S. MATHUR1 & B. K. TAN2

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1

Cambridge IVF, Box 123 Addenbrooke’s Hospital, Cambridge, UK and 2Associate Clinical Professor of Obstetrics and Gynaecology, University of Warwick, Coventry, CV4 7AL, UK

Introduction

et al., 2000). ‘Early’ OHSS occurs within 9 days of hCG administered for final follicular maturation and reflects the effect of exogenous hCG on a background of excessive ovarian response to FSH. ‘Late’ OHSS occurs 10 or more days after the ovulatory dose of hCG and, in the absence of luteal hCG administration, reflects the effect of endogenous hCG from an early pregnancy. ‘Late’ OHSS is significantly more likely to be severe than ‘early’ OHSS (Mathur et al., 2000).

Ovarian hyperstimulation syndrome (OHSS) is a potentially serious iatrogenic complication of supraphysiological ovarian stimulation, occurring most often in assisted conception cycles where the ovaries are stimulated to promote the development of multiple ovarian follicles and thereby increase the number of oocytes available. The incidence of moderate or severe OHSS has been reported to lie between 3.1% and 8% of IVF cycles (Delvigne & Rozenberg, 2002a). Much less commonly, OHSS may develop following ovulation induction with gonadotrophins or clomifene. A study utilising hospital discharge statistics from Finland in the period 1996 and 1998 identified hospitalisation due to OHSS following 0.04% of ovulation induction cycles and 0.9% of IVF cycles (Klemetti et al., 2005). This review examines the evidence for various methods of prevention of OHSS. Awareness of the pathogenesis of OHSS underpins effective prevention – a separate review discusses pathophysiology, clinical features and management of OHSS (Tan & Mathur, 2013). In particular, the critical role of human chorionic gonadotrophin (hCG) as the trigger for OHSS is wellrecognised. The action of HCG on ovarian granulosa cells, on a background of increased ovarian sensitivity and/or excessive ovarian response, leads to the excessive release of vascular endothelial growth factor (VEGF) and a variety of pro-inflammatory cytokines, which act as effector molecules to produce the characteristic features of OHSS. Exogenous HCG is commonly used as a surrogate for luteinising hormone (LH) to achieve final follicular maturation. Endogenous HCG arises from the trophoblast in cycles where conception occurs. The time of onset of OHSS reflects the effect of hCG exposure at different stages of the treatment process and may identify two distinct clinical presentations with different predictive factors and potential for severity (Mathur

Prediction of OHSS Pre-treatment patient characteristics Young age, polycystic ovaries and a previous history of OHSS have all been considered to increase the risk of developing OHSS (Delvigne & Rozenberg 2002a; Enskog et al., 1999; Navot et al., 1992). Navot et al. (1992) noted a lower mean body weight among women with OHSS compared to controls, but this was not confirmed by a larger study (Delvigne et al., 1993). More recently, the development of accurate ovarian reserve parameters provides further opportunity to identify patients at increased risk of developing OHSS. Serum concentrations of anti-Mullerian hormone (AMH) are closely predictive of the ovarian response to stimulation with exogenous gonadotrophins. La Marca et al. (2007) found that patients who had cycle cancellation due to a perceived high risk of OHSS had AMH levels in the highest quartile for their population. Nardo et al. (2009) found serum AMH to have a moderate degree of predictive ability for extremes of ovarian response. Lee et al. (2008) examined the ability of AMH to predict OHSS in a study of 274 GnRH agonist cycles with HCG luteal support. They showed that serum AMH concentrations were better predictive of the risk of developing OHSS than patient age, BMI or ovarian response parameters. The best balance

Correspondence: Mr Raj Mathur, Cambridge IVF, Box 123 Addenbrooke’s Hospital, Cambridge, CB2 2QQ, UK. Tel: ⫹ 44 (0)1223-349010. Fax: ⫹ 44 (0)1223-348202. E-mail: [email protected]

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of sensitivity and specificity was obtained by an AMH concentration of 3.36 ng/ml (DSL assay) (sensitivity 90.5%, specificity 81.3%, positive predictive value 29.7 and negative predictive value 99.0) (Lee et al., 2008). Recognition of the predictive value of pre-treatment serum AMH concentrations has led to the development of AMH-based tailored ovarian stimulation protocols. Yates et al. (2011) and Nelson et al. (2009) described their results using serum AMH to select women with a high risk of developing OHSS for GnRH antagonist protocols with a starting dose of 150 IU FSH daily. Nelson et al. (2009) carried out a prospective cohort study between two centres, one of which used GnRH agonist and the other GnRH antagonist to control LH during ovarian stimulation with high AMH concentrations. Hospitalisation for OHSS was required in 20 out of 148 women receiving GnRH agonist (13.9%) compared to 0 out of 34 women receiving GnRH antagonist, albeit in a different centre. The authors concluded that pre-treatment serum AMH levels could be used to individualise the treatment regime and thereby reduce the risk of OHSS. Yates et al. compared retrospectively 346 cycles of IVF based on a conventional protocol using serum FSH and age to guide stimulation, with 423 cycles using an AMH-guided stimulation protocol. In the conventional group, long protocol GnRH agonist was used in most cases, while, in the AMH-guided group, women with high AMH levels received GnRH antagonist and 150 IU FSH daily. The introduction of AMH-guided ovarian stimulation was associated with a reduced incidence of cycle cancellation or ‘freeze-all’ due to a perceived risk of OHSS, although the incidence of hospital admission due to severe OHSS did not differ significantly between the two groups. The number of small antral follicles visible on transvaginal ultrasound scan (antral follicle count (AFC)) has also been shown to correlate with the ovarian response to stimulation and the risk of developing OHSS. A prospective single-centre study found that the incidence of OHSS was 2.2% in women with an AFC ⬍ 24 and 8.6% in women with AFC ⱖ 24 (Jayaprakasan et al., 2012). The efficacy of AFC in predicting excessive ovarian response (defined as the collection of 20 or more oocytes) was identified by Kwee et al. (2007), who found that an AFC of 14 yielded the best combination of sensitivity (82%) and sensitivity (89%) with a positive predictive value of 58. Analogous to the situation with AMH, AFC has been studied as a guide to individualising ovarian stimulation regimes (Yovich et al., 2012), although prospective randomised data are similarly lacking. Ovarian response parameters Monitoring of the ovarian response to stimulation during a treatment cycle may provide an additional opportunity to identify cycles at high risk of developing OHSS. Among the features reported to be associated with a high risk of OHSS are high serum concentrations of

oestradiol (E2) (Enskog et al., 1999; Asch et al., 1991), large numbers of follicles (Blankstein et al., 1987; Enskog et al., 1999) and a large number of oocytes retrieved (Asch et al., 1991). However, despite their widespread use in clinical practice, ovarian response parameters have modest predictive value and there is significant variation between clinicians concerning cut-off levels to guide practice. A significant proportion of cases of severe OHSS occur in cycles where no risk factors were identified in the antecedent treatment cycle or patient characteristics (Delvigne et al., 1997), while the incidence of severe OHSS in cycles considered ‘high-risk’ by commonly used predictive variables is around 20% (Orvieto, 2005). Hence, any treatment cycle in which supraphysiological ovarian stimulation is used should be considered at risk of OHSS. Where ovarian response parameters are used to target preventative measures, it should be recognised that these parameters are unable to predict all cases of severe OHSS and that the cut-offs used are often arbitrary.

Preventative measures Alternatives to gonadotrophins As gonadotrophin therapy inevitably carries an element of risk of OHSS, an important aspect of prevention of OHSS is to consider alternative management options, depending on the clinical features. In cases of ovulatory dysfunction, life style modification may be appropriate to optimise weight or avoid excessive exercise. Clomifene, insulin-sensitising agents, aromatase inhibitors, laparoscopic ovarian diathermy, gonadotrophin-releasing hormone pump and antidopaminergic agents are appropriate in certain cases. The risk of OHSS is a further reason not to progress to IVF until indicated and only after consideration of other treatments. In vitro maturation of oocytes obtained from unstimulated ovarian follicles is an alternative to ovarian stimulation with gonadotropins in some women with PCOS. The avoidance of exogenous gonadotrophin (apart from a single dose of HCG 34–36 h prior to oocyte retrieval) makes the process much safer than standard IVF with regard to the risk of OHSS. However, the efficacy of IVM in terms of achieving a live birth remains lower than stimulated IVF in women with PCO (Gremeau et al., 2012; de Ziegler et al., 2012). Monofollicular ovulation induction Ovulation induction protocols should be individualised and monitored to achieve monofollicular development. Patients with PCOS display high sensitivity to gonadotrophins putting them at increased risk of OHSS. If the gonadotrophin dose oversteps the threshold of the polycystic ovary, this increases the risk of multifollicular development and hence OHSS (Homburg & Howles, 1999). Human Fertility


Prevention of OHSS 259 Regimes for monofollicular ovulation induction

Ovarian stimulation regimes

In the step-up protocol, stimulation is initiated with a low dose of FSH, for example 75 IU for 14 days followed by incremental increases of 37.5 IU every 7 days if there is no ovarian response (no follicle ⬎ 10 mm diameter) (Balasch et al., 2001) or 50 IU daily for 14 days, followed by increments of 25 IU every 7 days if no response is obtained (Christin-Maitre & Hugues, 2003). The dose that initiates follicular development is continued until the criteria for giving hCG are attained. In the step-down protocol, the starting dose is higher (for instance, 150 IU) and is decreased once ovarian response is. Randomised trials show a lower risk of overstimulation with the step-up as compared to the step-down protocol (Balasch et al., 2001; ChristinMaitre & Hugues, 2003). In a randomised control study of 83 women with clomifene-resistant PCOS (ChristinMaitre & Hugues, 2003), the step-up protocol was more efficient in obtaining a monofollicular development and ovulation than the step-down protocol. Although the duration of stimulation was longer, overstimulation was significantly less frequent using the step-up protocol (4.7% vs 36%, p ⬍ 0.0001). This is distinct from the risk of actual OHSS, for which comparative data are scant, although there is a reasonable expectation that the lower risk of ovarian overstimulation with the step-up protocol will be reflected in a lower risk of OHSS. A systematic review found a reduction in the incidence of OHSS with the use of purified urinary-derived FSH (uFSH) compared to hMG in ovulation induction cycles without the concomitant use of a GnRH agonist (OR 0.20, 95% CI 0.08–0.46) and a higher overstimulation rate when a GnRH-agonist was added to gonadotrophins (OR 3.15, 95% CI 1.48–6.70) (Nugent et al., 2000). A systematic review of three randomised trials in clomifene-resistant, anovulatory women found no significant difference in the occurrence of OHSS between recombinant FSH and uFSH (OR 1.55,95% CI 0.50–4.84) (Bayram et al., 2001).

Starting dose of FSH

Prevention of OHSS in IVF treatment Laparoscopic ovarian diathermy Laparoscopic ovarian diathermy has been studied as a measure to prevent OHSS in women with PCOS undergoing IVF. A controlled trial in women with ultrasound evidence of PCO found a lower risk of cancellation due to over-response, but no difference in the incidence of OHSS, with the use of laparoscopic ovarian diathermy carried out 1 week prior to the start of gonadotrophin stimulation in GnRH agonist cycles (Rimington et al., 1997). Similar results were found in a retrospective study by Tozer et al. (2001). The specific role of this invasive procedure to prevent OHSS in IVF is unclear. At present, data do not justify routine use of ovarian diathermy for the sole indication of prevention of OHSS in future IVF treatment. © 2014 The British Fertility Society

The starting dose of FSH for controlled ovarian hyperstimulation should take into account factors that may increase the risk of evoking an excessive ovarian response, including the presence or absence of PCO, previous history of OHSS and young age. The value of AMH and AFC in determining the appropriate starting dose and regime is described above. There are no randomised trials examining a lower starting dose of FSH for patients with risk factors for excessive ovarian response undergoing IVF. Marci et al. (2001) observed a significant reduction in cycle cancellation rate with a starting dose of 75 IU rFSH in 61 women who had previously responded excessively to a starting dose of 150–225 IU hMG. The incidence of OHSS was not reported in the study, but commonly used risk parameters (peak oestradiol and number of oocytes) were reduced in the group with the lower starting dose. Choice of FSH Meta-analysis of 32 trials with 7740 patients shows that the risk of OHSS in IVF cycles using urinary FSH is not significantly different to the risk in cycles using recombinant FSH (OR 1.18, 95% CI 0.86–1.61) (van Wely et al., 2011). GnRH agonist versus GnRH antagonist Prevention of a spontaneous LH surge in assisted conception cycles can be achieved either with gonadotrophinreleasing hormone agonists (GnRH-a) or antagonists. GnRH antagonists are associated with a shorter duration of stimulation, lower oestradiol levels and smaller numbers of follicles recruited (Tarlatzis et al., 2006). Al-Inany et al. (2011) performed a meta-analysis of randomised controlled trials comparing GnRH antagonist with long protocol GnRH agonist treatment cycles. OHSS was a secondary outcome in the studies included in the metaanalysis and there was no standard definition of OHSS between studies. GnRH antagonist was administered by any of three types of protocols – single dose, multiple dose flexible and multiple dose fixed. In women randomised to GnRH antagonist, ovarian stimulation was started on day 2 or 3 of the menstrual cycle and the antagonist started in most trials on stimulation day 6. Final follicular maturation was induced with 10,000 IU HCG. No significant difference in ongoing pregnancy or live birth rates was observed between GnRH antagonist and GnRH agonist cycles. Information on the incidence of severe OHSS was available in 29 studies with a total of 5417 subjects. The incidence of severe OHSS was significantly lower in GnRH antagonist cycles compared to GnRH agonist cycles (2.65% vs 6.61%; R.D ⫽ ⫺ 0.03, 95% CI ⫽ ⫺ 0.05 to ⫺ 0.02; p ⬍ 0.00001; I2 ⫽ 67.68%, 95% CI ⫽ 52.50–78.02%). In the overall study population, the risk of OHSS was 60% lower in


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women receiving GnRH antagonist, with an absolute risk reduction of 4% and a corresponding number needed to harm of 25. When women with PCOS were considered separately (8 trials, 783 women), the effect was even more marked. The incidence of severe OHSS among women with PCOS was significantly lower with the use of GnRH antagonist (3.44% vs 15.02%; R.D ⫽ ⫺ 0.10, 95% CI ⫽ ⫺ 0.14 to ⫺ 0.07; p ⬍ 0.00001; I2 ⫽ 82.05%, 95% CI ⫽ 65.82%–90.57%). A separate meta-analysis by Pundir et al. (2011) also showed a significant reduction in the risk of OHSS with the use of GnRH antagonist protocol in women with PCOS, when moderate and severe OHSS were pooled but not when either moderate or severe OHSS cases were considered separately. The incidence of coasting or cycle cancellation due to a perceived risk of OHSS was also significantly lower in GnRH antagonist cycles, lending further plausibility to the reduced incidence of OHSS with this method of treatment (Al-Inany et al., 2011). Despite evidence supporting a role for GnRH antagonists in reducing the risk of OHSS, the uptake of this method of controlling endogenous LH remains non-uniform. One reason for this may be that clinicians fear a reduction in IVF live birth rates if they change to a new regime. Several authors describe a ‘learning curve’ in the application of GnRH antagonist and we surmise that this may have inhibited wider adoption of this risk-reduction strategy (Merviel et al., 2005; Kamath et al., 2008; Al-Inany et al., 2011). It should be recognised also that the use of GnRH antagonist with a conventional HCG trigger does not abolish the risk of OHSS. In a large cohort of 2524 GnRH antagonist cycles in 1801 women, Papanikolaou et al. (2006) noted an incidence of hospitalisation for OHSS of 2.1% per cycle, which is broadly comparable to the incidence of OHSS of all grades of 3.3% noted by Mathur et al. (2000) in a series of 2362 consecutive GnRH agonist cycles in 1565 women. GnRH agonist for final follicular maturation in GnRH antagonist cycles In women receiving GnRH antagonist, the pituitary gonadotrophs retain their sensitivity to GnRH. Hence, administration of GnRH agonist to a woman receiving GnRH antagonist can induce an endogenous LH surge by their initial ‘flare’ effect. This surge may be sufficient for final follicular maturation, while carrying a lower risk of inducing OHSS than an injection of HCG, which has a longer half-life and produces more sustained luteotrophic stimulation than LH (Humaidan et al., 2012). Several trials in women undergoing IVF using a GnRH antagonist regime have compared the efficacy and safety of a GnRH agonist trigger to complete follicular maturation against a conventional HCG trigger. A meta-analysis of five randomised controlled trials comprising 504 fresh autologous cycles found a significantly lower risk of OHSS with a GnRH agonist trigger compared with HCG trigger (OR 0.10, 95% CI

0.01–0.82), suggesting that for a population with an OHSS incidence of 3% using HCG trigger, the incidence using GnRH agonist trigger would be 0–2.6%. The incidence of OHSS in egg donation cycles (3 trials, 342 cycles) was also significantly lower with GnRH agonist trigger compared to HCG trigger (OR 0.06, 95% CI 0.01–0.31) (Youssef et al., 2011a). However, the meta-analysis also found significantly lower live birth rates (OR 0.44, 95% CI 0.29–0.68; 4 trials comprising 497 cycles) and increased risk of miscarriage (OR 1.89, 95% CI 1.11–3.21; 8 trials comprising 713 cycles) with GnRH agonist trigger compared to HCG trigger in autologous IVF cycles. No difference was found in ongoing pregnancy or live birth rates in egg donation cycles indicating that where the transfer of fresh autologous embryos is not planned, GnRH agonist trigger has an advantage over HCG trigger in women undergoing IVF with GnRH antagonist. The lower clinical pregnancy rate following fresh autologous embryo transfer in GnRH antagonist cycles with GnRH agonist trigger is probably related to luteal insufficiency caused by reduced LH concentrations in the early and mid-luteal phase (Humaidan et al., 2012) and is a major factor limiting the uptake of this strategy to prevent OHSS. Attempts have therefore been made to develop luteal phase regimes that aim to correct this defect. One approach has been to use a small dose of HCG either at the time of GnRHa trigger (so-called ‘dual trigger’) or at the time of egg retrieval. In a randomised controlled trial of 302 patients, Humaidan et al. (2010) found that 1500 IU HCG administered 35 h after the GnRHa trigger was associated with no cases of OHSS and live birth rates comparable to a conventional HCG trigger in unselected women undergoing IVF with a GnRH antagonist regime. However, the safety of HCG administration, even in small doses, in women at high risk of OHSS may cause unease to clinicians. A recent retrospective study of 23 women at increased risk of OHSS (mean oestradiol level 4891 ⫾ 2214 pg/ml, mean number of ⬎ 12 mm follicles 20 ⫾ 6 on the day of trigger) found severe early OHSS in six patients (26%) with the use of GnRH agonist trigger and 1500 IU HCG luteal rescue (Seyhan et al., 2013). In contrast, a retrospective report of GnRH agonist trigger with 1500 IU HCG administered after oocyte retrieval in 275 cycles in women judged to be at high risk of OHSS from assessment of baseline characteristics found severe OHSS in 2 cycles (0.72%) and a pregnancy rate of 41.8% (Iliodromiti et al., 2013). Other regimes to correct the luteal phase defect following GnRh agonist trigger include intensive steroid replacement (intramuscular progesterone and transdermal or oral oestradiol) (Babayof et al., 2006; Engmann et al., 2008), recombinant LH injections during the luteal phase (Papanikolaou et al., 2011) and daily intranasal GnRH agonist during the luteal phase (Pirard et al., 2006). The present literature does not provide sufficient evidence of the efficacy and safety of any one regime (Humaidan et al., 2011; Humaidan et al., Human Fertility

Prevention of OHSS 261 2012). Further large prospective studies are required to determine the optimum regime to achieve a low risk of OHSS and high clinical pregnancy rates in highrisk women receiving GnRH agonist trigger in GnRH antagonist cycles.


Recombinant LH for final follicular maturation The luteotropic effect of hCG is more prolonged than that of endogenous LH, hence it has been suggested that using LH instead of hCG for final follicular maturation may reduce the risk of OHSS. However, a metaanalysis of 2 trials comprising 280 subjects comparing recombinant LH with urinary hCG did not show any difference in the risk of severe OHSS (OR 0.82, 95% CI 0.39–1.69) (Youssef et al., 2011b). The incidence of severe OHSS was quite high in both groups (10.3% in the rLH group and 12.4% in u-hCG group). Further trials are needed to assess the efficacy of rLH in reducing the risk of OHSS. Recombinant hCG for final follicular maturation Meta-analysis of 3 RCTs comprising 549 subjects found no significant difference in the incidence of severe OHSS between recombinant and urinary hCG used for final follicular maturation (3.3% vs 1.9%, OR 1.49, 95% CI 0.37–4.10) (Youssef et al., 2011b). Dose of hCG Pregnancy rates and numbers of oocytes retrieved in IVF treatment appear not to be different for doses of HCG ⱖ 5000 IU (Abdalla et al., 1987). Given the correlation between degree of HCG exposure and the risk of OHSS (Mathur et al., 1995), it appears sensible to use the lowest effective dose of HCG for final follicular maturation in cycles considered at risk of OHSS. Nargund et al. (2007) described the use of 2500 IU HCG to induce final follicular maturation in a group of 21 women thought to be at high risk of OHSS (⬎ 20 follicles in each ovary and E2 ⬎ 14000 pmol/l on the day of HCG). Despite the transfer of fresh embryos, no cases of moderate or severe OHSS were noted. Clinical pregnancies occurred in 13 cycles (61%) with 2 twin pregnancies. This small study suggests that, in cycles with an excessive ovarian response, even a very low dose of urinary HCG of 2500 IU may be sufficient to obtain good clinical results with a low risk of significant OHSS. A trial by Chang et al. (2001) in women receiving either 250 mcg or 500 mcg of recombinant HCG for follicular maturation showed a lower risk of severe OHSS with the 250 mcg dose. Coasting Coasting consists of withholding gonadotrophins while maintaining pituitary suppression. Daily serum E2 estimation and follicular tracking are carried out until E2 drops to a “safe” level. HCG is then administered, followed by oocyte retrieval and embryo transfer. © 2014 The British Fertility Society

Serum FSH levels decline significantly during the coasting period. Larger follicles have a lower dependence on FSH than smaller follicles and are capable of continuing their growth and maturation, while small and intermediate follicles undergo atresia (Benavida et al., 1997; Dhont et al., 1998). FSH is a potent inhibitor of granulosa cell apoptosis (Chun et al., 1996), which may increase as FSH concentrations fall (Tortoriello et al., 1998). Declining concentrations of vasoactive mediators of ovarian origin, such as VEGF, may contribute to the efficacy of coasting (Tozer et al., 2004). A Cochrane review (D’Angelo et al., 2011) identified four randomised trials of coasting, but only one of these compared coasting with no coasting, showing a reduction in the risk of moderate or severe OHSS with coasting (OR 0.17, 95% CI 0.03–0.88; P ⫽ 0.03). Other trials either compared coasting with early follicular aspiration or GnRH antagonist administration, and no significant difference was found in the incidence of OHSS in these comparisons. Owing to the comparison with another preventative modality, these trials may not be a true reflection of the value of coasting itself. There are several retrospective studies examining the value of coasting in preventing OHSS. In a qualitative systematic review of 12 studies involving 493 patients, the data were heterogenous with variable criteria being employed for coasting. The fertilisation and pregnancy rates were acceptable and 2.5% of patients required hospitalisation for OHSS (Delvigne & Rozenberg, 2002b). While it is clear that coasting does not abolish the risk of OHSS, there does appear to be a lower incidence of OHSS in coasted cycles than would be expected from the literature (García-Velasco et al., 2006). Mansour et al. (2005) reported their experience of a large retrospective series of cycles in which coasting was initiated if there were ⱖ 20 follicles and E2 ⱖ 3000 pg/ml. Of 1223 cycles with coasting, 16 cases of severe OHSS occurred (1.3%), all in cycles where hCG was administered prior to the E2 dropping below 3000 pg/ml. A survey of 573 members of the European Society of Human Reproduction and Embryology found coasting to be the commonest preventive strategy used (Delvigne & Rozenberg, 2001). Coasting can be initiated once follicles are mature (⬎ 15 mm). The criteria described for initiating coasting are variable but are intended to identify cycles where the ovarian response is so excessive that cycle cancellation would otherwise be considered. Most investigators have recommended using E2 levels as one of the criteria for initiating coasting, despite their relatively modest predictive value for severe OHSS. Cut-off levels have varied from 2500 pg/ml (Dhont et al., 1998) to 6000 pg/ml (Egbase et al., 1999). It is not possible to be prescriptive about the precise E2 cut-off that should be used for initiating coasting, hence the experience of the individual centre and an overall assessment of the risk of OHSS in any given treatment cycle should be taken into account. The number of follicles is also a criterion described by most investigators, with some variation in


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the cut-off numbers used and whether the total number of follicles or the number of mature follicles only is considered. Criteria for when coasting may cease, followed by the administration of hCG usually relate to a drop in serum E2 level to a ‘safe’ level, usually below 3500 pg/ml (García-Velasco et al., 2006) or 3000 pg/ml (Mansour et al., 2005). An abrupt drop in E2 or a level ⬍ 1000 pg/ml may be associated with poor outcome (GarcíaVelasco et al., 2006). Coasting for more than 3 or 4 days may be associated with poorer cycle outcomes, although clinical pregnancies are still achieved. In a retrospective analysis of 1223 coasted cycles, Mansour et al. (2005) found a lower clinical pregnancy rate following ICSI in cycles that were managed with coasting for ⬎ 3 days compared to cycles where E2 had declined to safe levels within 3 days of coasting (36% vs 52%). García-Velasco et al. (2006) found lower implantation rates in patients who had been coasted for ⬎ 4 days (15.5% vs 28.5%). However, a retrospective analysis of 1058 cycles where coasting was applied did not find a reduction in live birth rate with coasting up to 8 days. Neither peak oestradiol concentration nor the drop in oestradiol with coasting was predictive of cycle outcome (Abdalla & Nicopoullos, 2010). At present it is not possible to be prescriptive about setting limits on coasting in terms of time or fall in oestradiol concentration. Avoiding HCG Cycle cancellation OHSS develops only in cycles with exposure to endogenous or exogenous hCG. Consequently, the most effective prevention is to withhold hCG in cycles at risk of OHSS, thereby cancelling the treatment cycle. The emotional and financial costs of this can be significant, leading to an understandable reluctance on the part of patients to let the ovarian response go to waste. However, there remains a role for cancellation in circumstances where the ovarian response is excessive and embryo cryopreservation is not a viable option, particularly if the gonadotrophin dose can be reduced for future attempts. Patients need to be counselled with regard to their individual risk of developing OHSS, with its potential morbidity, as well as the risk of developing a similar ovarian response even with a lower dose of gonadotrophins. Cryopreservation of all embryos Avoiding fresh embryo transfer eliminates exposure to endogenous hCG of pregnancy and should thereby eliminate the possibility of late OHSS. Clearly, it cannot prevent early OHSS which is related to the pre-ovulatory exogenous HCG. Despite its theoretical value and widespread use in practice, cryopreservation of all embryos has been poorly studied as a means of preventing OHSS. A Cochrane review (D’Angelo & Amso, 2002) found only two studies suitable for inclusion,

of which one (Shaker et al., 1996) compared embryo cryopreservation with intravenous albumin and subsequent fresh embryo transfer. The only trial comparing cryopreservation of all embryos with fresh embryo transfer alone (Ferraretti et al., 1999) found a lower incidence of OHSS in the group where all embryos were cryopreserved compared to the fresh embryo transfer group (0/58 vs 4/67), but the difference did not reach statistical significance. All patients in this trial received 20 g albumin intravenously on the day of oocyte retrieval. Endo et al. (2002) in a controlled trial of 138 women undergoing elective cryopreservation of all embryos due to excessive ovarian response found that the incidence of OHSS was reduced by the continuation of GnRH agonist for 1 week after hCG injection. Increased application of blastocyst culture and vitrification may allow clinicians more time to observe the patient for signs of early OHSS before a decision needs to be made between freezing all embryos and fresh embryo transfer. A step-by-step algorithmic approach has been proposed (D’Angelo, 2010).

Adjuvant treatments Metformin co-treatment during gonadotrophin stimulation The elevated risk of OHSS following ovarian stimulation in women with PCOS has been correlated to elevated VEGF activity (Peitsidis & Agrawal, 2010). Studies on cultured vascular smooth muscle cells reveal that insulin stimulates VEGF protein expression and secretion (Doronzo et al., 2004), pointing to a possible pathophysiologic link between insulin resistance and OHSS in women with PCOS. Investigators have studied the use of metformin co-treatment during ovarian stimulation in order to improve the ovarian response and reduce the risk of OHSS. In oocytes retrieval to women with PCOS undergoing IVF. Coasting was not carried out and embryo cryopreservation with delayed transfer was offered if 30 or more oocytes were obtained. The incidence of severe OHSS was significantly reduced in the metformin group (2/52 vs 10/49; OR 0.15, 95% CI ⫽ 0.03–0.76). A systematic review pooling data from five RCTs in women with PCOS undergoing a randomised controlled trial, Tang et al. (2006) administered placebo or Metformin 850 mg twice daily from the first day of down-regulation to the day of IVF (Tso et al., 2009) showed a significant reduction in the incidence of OHSS with the use of metformin (13/227 vs 47/222; OR 0.27, 95% CI ⫽ 0.16–0.47), without significant statistical heterogeneity. There was no statistically significant difference in markers of ovarian response or treatment outcome with the use of metformin. Only one trial (Doldi et al., 2006) examined the use of metformin in combination with a GnRH antagonist regime, studying 40 women with PCOS randomised to no pre-treatment or metformin 1.5 g daily for 2 months prior to the start of IVF. The incidence of Human Fertility

Prevention of OHSS 263 OHSS was 5% in the metformin group vs 15% in the placebo group (p ⬍ 0.05).


Dopamine agonists Dopamine agonists have been proposed as a preventative measure for OHSS, based on the action of dopamine in antagonising the vascular permeability-enhancing effect of VEGF through the dopamine receptor type 2. Initial studies in rats were followed by a trial in oocyte donors (Alvarez et al., 2007a), which showed a reduced incidence of moderate, but not severe, OHSS in oocyte donors receiving 0.5 mg cabergoline daily from the day of HCG administration for 8 days. Cabergoline appears to inhibit the permeability-enhancing effect of VEGF without affecting neo-vascularisation, enabling implantation to occur (Alvarez et al., 2007b). Carizza et al. (2008) carried out a randomised controlled trial of cabergoline 0.5 mg orally daily from the day after oocyte retrieval for 21 days versus no treatment in 166 women with E2 levels ⬎ 4000 pmol/l on the day of HCG administration. The incidence of early, but not late, OHSS was significantly reduced in the cabergoline group. A subsequent systematic review (Youssef et al., 2010) confirmed a reduced risk of early, but not late, OHSS in women treated with cabergoline (OR 0.1, 95% CI 0.03–0.33). It should be noted that late OHSS is more likely to be clinically severe and prolonged than the early form. A further randomised trial comparing cabergoline and hydroxyl-ethyl starch with hydroxyl-ethyl starch alone in women at increased risk of OHSS did not find any difference in the incidence or severity of OHSS between the two groups (Matorras et al., 2013). At present, the data do not support a major role for cabergoline in preventing severe or late OHSS, which are the clinical groups of patients most at risk of complications. Intravenous albumin Administration of intravenous albumin around the time of oocyte retrieval has been proposed as a measure to prevent OHSS, starting initially with a report of effectiveness in an uncontrolled case series (Asch et al., 1993). This was followed by a number of randomised controlled trials of small numbers of patients deemed to be at risk of OHSS on the basis of parameters of ovarian response, which appeared to show a reduction in the incidence of severe OHSS in the group receiving albumin. However, the evidence from meta-analysis of randomised trial remains unclear. A Cochrane review (Youssef et al., 2011c) found a lower incidence of OHSS with the use of albumin (OR 0.67, 95% CI 0.45–0.99; P ⫽ 0.01). However, a separate meta-analysis (Venetis et al., 2011) did not show any difference in the incidence of severe OHSS between women receiving intravenous albumin and controls. The authors of the Cochrane review acknowledged the presence of significant heterogeneity, methodological limitations in the studies assessed and small numbers of subjects in individual trials. If © 2014 The British Fertility Society

unpublished studies were excluded from the Cochrane review, there was no significant difference in the risk of OHSS between patients receiving intravenous albumin and controls (OR 0.75, 95% CI 0.47–1.21). The largest single-centre trial on this subject (Bellver et al., 2003) reported on 976 women who had 20 or more oocytes collected. Subjects were randomised to receive 40 g intravenous albumin immediately after oocyte retrieval or no treatment. Patients were followed up until menstruation or the detection of foetal heart activity. The incidence of moderate and severe OHSS or severe OHSS alone did not differ significantly between the two groups (7.1% moderate and severe and 5% severe in the albumin group; 6.7% moderate and severe and 4.7% severe in the control group). The study was powered to detect a 50% reduction in the incidence of severe OHSS with 95% confidence and a type 2 error of ⫾ 2.4%. The balance of the literature therefore does not support a benefit for intravenous albumin administered around the time of oocyte retrieval in preventing OHSS. The proposed mechanism for the putative effect of albumin in preventing OHSS is unclear: it has been suggested that albumin may bind to vaso-active mediators, such as VEGF, but this has not been substantiated. Serum VEGF levels on the day of embryo transfer did not differ significantly between highly responsive patients who went on to develop OHSS and patients with a similar ovarian response who did not develop OHSS (Mathur et al., 2002). The effect of albumin in maintaining plasma oncotic pressure and hence intravascular volume may be useful in mitigating the pathophysiology of established severe OHSS, but it is unclear how this action would prevent the development of OHSS. Albumin is a blood-derived product with a significant cost. Side-effects of albumin administration, though usually mild, include allergic reactions, nausea and vomiting. Given these factors it appears that the routine use of albumin with the purpose of prevention of OHSS is not justified. Hydroxy-ethyl starch Hydroxy-ethyl starch (HES) is a large molecular weight synthetic compound used as an alternative plasma volume-expander to albumin. A group of investigators reported its use to prevent OHSS in 100 high-risk women who were administered 6% HES in the dose of 1000 ml at the time of oocyte retrieval and 500 ml at embryo transfer (Graf et al., 1997). There was no significant difference in the incidence of severe OHSS between the treatment group and a historical control group with a similar risk profile for OHSS, although the incidence of moderate OHSS was reduced. A subsequent placebocontrolled randomised trial assessed the effectiveness of 1000 ml 6% HES administered at the time of embryo transfer in women thought to be at high risk of OHSS (König et al., 1998). The incidence of moderate and severe OHSS in the control group was 13% (7/53),


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compared with 2% (1/51) in the treatment group, with the difference just reaching statistical significance (p ⫽ 0.03). The criteria for selecting patients for the trial were an oestradiol level greater than 1500 pg/ml (5505 pmol/l) or ⬎ 10 follicles on the day of hCG injection. Anecdotally, most UK clinics would not institute specific preventative measures for OHSS at this level of ovarian response. Gokmen et al. (2001) found albumin and HES to both be superior to placebo in preventing OHSS in women with oestradiol ⬎ 3000 pg/ml and ⬎ 20 follicles on the day of hCG. Although there was no significant difference in the incidence of OHSS between the albumin and HES groups, the authors preferred HES on the grounds of cost and safety. Given the small number of patients included in the trails involving HES and the experience with regard to albumin (see above), it seems prudent to await further research before HES is accepted as a routine agent for preventing OHSS.

Follicle aspiration prior to hCG administration It has been suggested that aspiration of some ovarian follicles prior to hCG administration may reduce the risk of OHSS by reducing the cohort of granulosa cells able to respond to HCG. In a retrospective study of 13 patients returning for further IVF following previous cycles complicated by OHSS, Zhu et al. (2005) found that this approach was associated with a reduction in the risk of OHSS. In contrast four of five patients developed severe OHSS following unilateral follicular aspiration and continuation of stimulation leading to oocyte retrieval (Schroder et al., 2003). No benefit was seen for aspiration of all follicles from one ovary 6–8 h prior to hCG in 16 high OHSS risk women compared to 15 matched controls who did not undergo the aspiration (Egbase et al., 1997). In patients at high risk of OHSS comparison between 15 coasting patients and 15 patients undergoing early aspiration revealed good pregnancy rates, but OHSS in 3 and 4 cases, respectively (Egbase et al., 1999). The evidence regarding timed follicular aspiration prior to hCG remains uncertain. The strategy involves an extra invasive procedure which may make it less acceptable to patients than coasting.

Choice of luteal support HCG has a critical role in precipitating OHSS and may worsen established OHSS. Progesterone is equally effective as hCG for luteal support and is associated with a lower risk of OHSS (van der Linden et al., 2011). Hence, luteal support should avoid hCG. The increased risk of OHSS in multiple pregnancies (Mathur et al., 1995) is further encouragement to adopt a policy of single embryo transfer in younger, more fertile women, who are also at a greater risk of OHSS. Some researchers recommend high-dose progesterone in the luteal phase as a means of steroidal ovarian suppression, with a view to reducing the incidence of

OHSS (Schwarzler et al., 2003). In a study of 945 consecutive IVF cycles, patients were randomly allocated to receive either hCG 5000 IU 4 and 8 days after embryo transfer or intramuscular hydroxyl-progesterone caproate 100 mg with oestradiol valerate 10 mg on days 2, 6, 10 and 14 after embryo transfer. The incidence of OHSS was significantly higher in the hCG group (30.5%) compared to the group that did not receive hCG (5.4%). It is difficult to rationalise that this difference is due to a specific protective effect of progesterone, rather than the impact of hCG on increasing the risk of OHSS.

Conclusion OHSS is a significant iatrogenic problem in women undergoing ovarian stimulation for fertility treatment. Predicting the risk of OHSS from patient characteristics and ovarian response is associated with significant false positives and false negatives. Of the number of measures proposed to prevent OHSS in IVF cycles, evidence supports a role for GnRH antagonist (with GnRH agonist trigger in cycles where fresh autologous embryo transfer is not required), metformin co-treatment for women with PCOS and the avoidance of hCG for luteal support. Coasting of overstimulated cycles and elective cryopreservation of all embryos are associated with a reduced risk of OHSS. However, no available method guarantees complete avoidance of OHSS, and there is little agreement on criteria for applying various preventative measures. Continued research is therefore required in this area. Future developments in in vitro maturation of oocytes, immunomodulation and a better understanding of the pathophysiology of OHSS may lead to an improvement in the ability to predict and prevent OHSS.

Guidelines See Figure 1 for classification of evidence levels and grades of recommendations. Alternatives such as lifestyle changes and clomifene should always be considered before proceeding to gonadotrophin treatment in suitable patients √ A low-dose step-up regime carries a lower risk of overstimulation compared with a step-down regime in women undergoing monofollicular ovulation induction A Ovarian stimulation regimes for IVF should be based on the predicted ovarian reserve B In women undergoing IVF, GnRH antagonist regimes carry a lower risk of OHSS than the use of GnRH agonist for pituitary suppression and should specially be considered in women at high risk of OHSS A In GnRH antagonist cycles where fresh autologous embryos are not to be transferred (for instance, in oocyte donors), final follicular maturation with GnRH agonist carries a lower risk of inducing OHSS than the use of HCG A Human Fertility


Prevention of OHSS 265

Figure 1.Classification of evidence levels and grades of recommendations.

Metformin co-treatment should be considered in women with PCOS undergoing IVF A Coasting in cycles with an excessive ovarian response is associated with a lower risk of OHSS. However, it is not possible to be specific about criteria for initiating and stopping coasting. B In cycles with an excessive ovarian response or where OHSS is manifest prior to embryo transfer, cryopreservation of all embryos abolishes the risk of late, but not early, OHSS. A HCG should not be used for luteal support. A Dopamine agonists may reduce the risk of early but not late OHSS in high-risk women. A Intravenous albumin or HES are not recommended as routine measures to prevent OHSS. A Cycle cancellation prior to HCG administration provides the only sure method of preventing OHSS. √ Declaration of interest: The authors report no declarations of interest. The authors alone are responsible for the content and writing of the paper. References Abdalla, H.I., Ah-Moye, M., Brinsden, P., Howe, D.L., Okonofua, F., & Craft, I. (1987). The effect of the dose of human chorionic gonadotropin and the type of gonadotropin stimulation on oocyte recovery rates in an in vitro fertilization program. Fertility and Sterility, 48, 958–963. Abdalla, S. & Nicopoullos, J. (2010). The effect of duration of coasting and estradiol drop on the outcome of assisted reproduction: 13 years of experience in 1,068 coasted cycles to prevent ovarian Hyperstimulation. Fertility and Sterility, 94, 1757–1763. Al-Inany, H.G., Youssef, M.A., Aboulghar, M., Broekmans, F.J., Sterrenburg, M.D., Smit, J.G., & Abou-Setta, A.M. (2011). Gonadotrophin-releasing hormone antagonists for assisted © 2014 The British Fertility Society

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