A new cohort study from a national US database confirms that a lower risk of OHSS is associated with increasing use of GnRH antagonists and agonist trigger and a freeze-all approach to avoid immediate pregnancy.
It’s now almost a decade since Paul Devroey and colleagues in Brussels set out their blueprint for an ‘OHSS-free’ clinic in ART.(1) Their proposal to ‘erase’ the syndrome rested on a GnRH antagonist protocol with agonist trigger and a policy to freeze all embryos for later use. Just a few months earlier the reproductive endocrinologist Georg Griesinger had reported a multicentre trial in which agonist triggering with cryopreservation was described as ‘efficacious and safe’, although a single case of a severe early-onset OHSS had occurred.(2)
Before that time, as a new cohort study from the CDC’s National Assisted Reproductive Technology Surveillance System (NASS) now shows, the proportion of ART cycles complicated by OHSS had been slowly rising, such that OHSS alongside multiple pregnancies were cited as the principal risks of ART. The number of cycles now reviewed by NASS totalled almost 2 million and included all fresh (autologous and donor) and embryo banking treatments performed between 2000 and 2015.(3)
The study first confirmed that the incidence of OHSS did increase between 2000 and 2006, from 9.96 to 14.34 cases per thousand, but thereafter began a decline to 5.27 per thousand in 2015. These rates were proportionately comparable for both moderate and severe OHSS, with severe cases increasing initially from 1.87 to 3.83 cases per thousand and thereafter declining to 1.06 cases per thousand in 2016. Although this trend, write the authors, is ‘encouraging’, there is still ‘considerable room for improvement in preventing OHSS’.
They add that the decline over the past decade and more ‘may reflect’ the increasing use of GnRH antagonist protocols and agonist trigger, treatment with metformin in PCOS cases, and a freeze-all approach to avoid immediate pregnancy – indeed, the essential components of Devroey’s segmentation principle. In its report of 2000 data ESHRE’s EIM consortium reported an aggregate prevalence (of moderate and severe OHSS) of 1.1%, while the incidence reported online at this year’s virtual annual meeting (for 2017 from incomplete submissions) had declined to 0.21% (2.1 cases per thousand cycles). However, said Christine Wyns presenting the figures, ‘we know that there is under-reporting here.’ In his report on global activity, David Adamson noted a rate of ‘moderate to severe’ OHSS of 11.5 cases per thousand retrievals in China in 2016, ‘very similar to international numbers’. In Australia and New Zealand, where cycle data is validated, 0.6% of cycles were complicated by OHSS in 2015.
If OHSS is to be eliminated – as Devroey envisaged – findings from the NASS cohort confirm the usual suspects of modifiable risk factors: the retrieval of more than 15 oocytes, pregnancy after fresh embryo transfer, and type of pituitary suppression. With pregnancy after an IVF cycle associated with an increased risk of OHSS, deferred embryo transfer, especially in patients at high risk of OHSS, may logically reduce that risk. There was also an association of higher risk – though not modifiable - with women under 30 and those with ovulatory disorders (including PCOS).
On the matter of ovarian stimulation, this NASS report, following the conclusions of recent studies (and consistent with the recommendations of ESHRE’s latest guidelines), advises IVF providers ‘that limiting COH in high responders may prevent OHSS without sacrificing live birth rate’. Even in normal responders, it went on, ‘a goal of retrieving 11-15 oocytes per cycle may produce an optimal live birth rate and limit the risk of OHSS’. Indeed, in the NASS cohort those cycles in which embryo banking was performed were 35% less likely to result in OHSS than cycles without embryo banking.
The NASS data in this study ends at 2016, and most of the likely explanations for the decline in OHSS – antagonist cycles with agonist trigger, embryo banking – are not extended into more recent years. The notion of registry cohorts running two or three years behind real life is a feature of such studies, but in this case the authors did detect a significant trend towards a lower incidence of severe OHSS as the proportion of embryo-banking cycles in a clinic increased. The likelihood that this trend is evident and even greater today was recognised by David Adamson in his global report, who proposed that the number of freeze-all cycles, while complicating the registries’ outcome calculation from an oocyte pick-up, was certainly an under-representation in his ICMART data for 2016.
So the true safety effect of freeze-all on the risk of OHSS may best be left to the randomised trials and meta-analyses, which generally support a lower risk of OHSS (even if not improved outcome in normal responders); for example, the risk of moderate/severe OHSS was significantly lower with deferred transfer than with fresh (RR 0.42) in the most recent meta-analysis published.(4) However, the latest randomised trial, which for the first time showed that deferred frozen single blastocyst transfer in normally ovulatory women did result in significantly higher rates of singleton live birth than from fresh transfers, failed to find any lower incidence of OHSS.(5) Both this trial and the meta-analysis had also found a higher risk of pre-eclampsia in the freeze-all subjects.
Nevertheless, despite the inconsistent trial results for LBR, and a still-to-be-explored risk of pre-eclampsia, freeze-all seems here to stay, whether on the basis of safety or improved efficacy. In the USA the Centers for Disease Control and Prevention (CDC) has described the escalation in elective FET as 'dramatic', plotting a rise from almost zero cycles in 2007 to 65,840 in 2016.(6) According to CDC, these cycles - variously identified as 'banking', 'freeze-all', or 'segmentation cycles' -accounted for 25% of all IVF/ICSI cycles in the USA in 2016. Similarly, Adamson in his global report described a huge increase in the number of freeze-all cycles in Japan, which elsewhere were estimated as 41% of all ART treatments in 2016.(7)
Nevertheless, the NASS report makes clear that embryo freezing in cases of moderate or high OHSS risk is only one of several measures to mitigate the risk. But considered ‘when appropriate’ alongside ‘careful controlled ovarian hyperstimulation with a goal of obtaining ~15 mature oocytes in all patients undergoing IVF, use of a GnRH antagonist and, when appropriate, a GnRH agonist trigger’, the risk of this ART complication can indeed be reduced.
1. Devroey P, Polyzos NP, Blockeel C. An OHSS-Free Clinic by segmentation of IVF treatment. Hum Reprod 2011; 26: 2593-2597. doi.org/10.1093/humrep/der251
2. Griesinger G, Schultz L, Bauer T, et al. Ovarian hyperstimulation syndrome prevention by gonadotropin-releasing hormone agonist triggering of final oocyte maturation in a gonadotropin-releasing hormone antagonist protocol in combination with a "freeze-all" strategy: a prospective multicentric study. Fertil Steril 2011; 95: 2029-2033.
3. Schirmer DA, Kulkarni AD, Zhang Y, et al. Ovarian hyperstimulation syndrome after assisted reproductive technologies: trends, predictors, and pregnancy outcomes. Fertil Steril 2020; doi.org/10.1016/j.fertnstert.2020.04.004
4. Roque M, Haahr T, Geber S. Fresh versus elective frozen embryo transfer in IVF/ICSI cycles: a systematic review and meta-analysis of reproductive outcomes. Hum Reprod Update 2019; 25: 2-14. doi.org/10.1093/humupd/dmy033
5. Wei D, Liu J-Y, Sun Y, et al. Frozen versus fresh single blastocyst transfer in ovulatory women: a multicentre, randomised controlled trial. Lancet 2019; 393: 1310-1318.
6. Centers for Disease Control and Prevention, American Society for Reproductive Medicine, Society for Assisted Reproductive Technology. 2016 Assisted Reproductive Technology National Summary Report.
7. Ishihara O, Jwa SC, Kuwahara A, et al. Assisted reproductive technology in Japan: A summary report for 2016 by the Ethics Committee of the Japan Society of Obstetrics and Gynecology. Reprod Med Biol 2019; 18: 7-16. DOI:10.1002/rmb2.12307