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Ovarian hyperstimulation syndrome – it's time to reverse the trend

5 December 2016
By Professor Geeta Nargund
Medical Director, CREATE Fertility
Appeared in BioNews 880

Severe ovarian hyperstimulation syndrome (OHSS) is a serious and potentially fatal condition caused by overstimulation of the ovaries by drugs during IVF treatment. It is preventable with the modern management of IVF cycles, and the incidence of the condition should therefore be falling precipitously to almost zero – as it is in many countries. Indeed, my own clinic has not had a case of severe OHSS for over 15 years. However, in its latest report on adverse incidents in fertility clinics, the Human Fertilisation and Embryology Authority (HFEA) noted a 'slight increase' in the number of severe OHSS incidents reported to it in 2015 (1). In fact, this statement obfuscates the significance of the matter – there has been a 40 percent rise in hospital admissions with severe OHSS in UK fertility clinics in 2015 (2). This is an extraordinary statistic. The HFEA should be putting this alarming statistic on the front page and discussing methods to reverse this trend. Yet the very opposite appears to be the case. It is impossible to extract the number of OHSS cases from this report and it has only come to light thanks to the persistence of Guardian science reporter Hannah Devlin (2).

Not only does the HFEA's report fail to state the number of OHSS cases admitted to hospital for the year, but the most serious type of OHSS usually occurs during pregnancy, following successful implantation of the embryo, and many of these cases may not have been reported to the HFEA. The report may not therefore present an accurate picture of OHSS incidents in the UK and there remain questions about whether any maternal deaths that may be linked to OHSS have been reported.

Severe OHSS – a life-threatening condition, sometimes requiring admission to intensive care – is not currently regarded by the HFEA as a 'Grade A' adverse incident. The death of a patient is a grade A incident, but a near-death iatrogenic incident apparently is not. Instead, severe OHSS is relegated to the second tier ('Grade B'), the same level as administrative errors, such as those 'resulting in breach of confidentially, where sensitive personal data or data relating to more than one patient is sent to the wrong recipient'. What's more, there is no mention of clinical protocols that could be used to prevent severe OHSS in the 'lessons to learn' section of the report. I must therefore seriously question whether the HFEA and its advisers are giving sufficient attention to the incidence of severe OHSS.

There remain areas for improvement in clinical practice. If the condition is induced by stimulation, then the use of a reduced dose of stimulation followed by GnRH agonist to trigger ovulation, with an option of cryopreservation of all embryos, will almost certainly minimise the risk, if not eliminate it completely (3). While this will mean abandoning the use of the 'long downregulation' protocol employed in many IVF treatment cycles, this is an old fashioned protocol anyway and changing to antagonist cycles will be in the woman's interest. 

Furthermore, any recommendation to a couple to have long downregulation and high-stimulation IVF necessitates full informed consent, in accordance with the Supreme Court ruling in Montgomery v Lanarkshire (4), and this means that the onus is on the clinician to provide a detailed explanation of the advantages and risks of any treatment. Consent forms may need to be altered appropriately to record this.

In the meantime, all long downregulation protocols should be stopped for those at risk of OHSS. A limit should be placed on the dose of FSH (follicle stimulating hormone) given to a woman, dependent on her history, her age, BMI (body mass index), AMH (Anti-Mullerian hormone) levels and antral follicle count. Information about stimulation protocols, drugs and dosages used during stimulation and implantation phases of IVF treatment, including off-label medications, should be collected and monitored.

To some extent, I have sympathy with the HFEA. It is motivated by the desire to help women and couples undergoing fertility treatment, but much like with 'add-ons' – recently the focus of adverse media publicity (see News) – the HFEA has not been given express powers to regulate which drugs can be used during IVF treatment and at what doses. Instead, it is trying to help by providing better information to patients. This is an issue on which Siobhain McDonagh MP is campaigning, and the HFEA should support her calls to amend legislation to give the HFEA powers to regulate this area and also to protect the welfare of women more widely (5).

For now, however, I do believe that the HFEA can do something more substantive to help. The simple reality is that the HFEA has the power to impose licence conditions and, in the past, it has used this ability to require clinics to adopt strategies to reduce multiple births. They could easily insist on a similar licence condition on the incidence of severe OHSS. But the responsibility does not solely fall on the HFEA. The Medicines and Healthcare products Regulatory Agency (MHRA), which is the regulatory body for medicines, must also get involved and take action to prevent this serious complication and the overuse of drugs. By this means, the welfare and safety of women undergoing IVF treatment would be more effectively protected. The time has now come for firm action to reverse the trend of severe OHSS.

1) Adverse incidents in fertility clinics: lessons to learn (2015)
HFEA |  6 October 2016
2) Increase in IVF complications raises concerns over use of fertility drugs
The Guardian |  13 November 2016
3) 3. Devroy, P. Polyzos, NP. and Blockeel, C. 'An "OHSS Free" clinic by segmentation of IVF treatment'.
Human Reproduction, 26 (10) 2593-7 |  9 August 2011
4) Montgomery (Appellant) v Lanarkshire Health Board (Respondent) (Scotland)
The Supreme Court |  11 March 2015
5) Commons Debates - IVF: Welfare of Women
House of Commons Hansard |  20 January 2016
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Well said ( - 05/12/2016)
As the author says, the figures are limited and it's not clear where the increase is coming from. I'd be very interested some more demographic information, eg to know the proportion of those women who are getting OHSS divided into patients, egg sharers and egg donors, and women freezing their own eggs.
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