Challenges of OHSS in modern reproductive medicine practice

INTRODUCTION

Ovarian hyperstimulation syndrome (OHSS) remains a significant complication of fertility treatment whenever ovarian stimulation is used to increase the number of eggs and embryos available. This condition has been known since the advent of gonadotropins for ovarian stimulation, and over the years there have been many advances in our understanding of its pathophysiology. We know now that OHSS is the end result of a complex interaction of cytokines and vaso-active molecules produced by hyperstimulated ovaries, with activation of secondary mediators as part of the process.^[1] To a limited extent, this has aided in the development of measures that reduce the chance of a woman developing OHSS, but the challenge remains to translate basic scientific knowledge into clinical treatment.

At the same time that understanding of the mechanisms of OHSS is improving, there have been advances in clinical reproductive endocrinology that are relevant to the incidence of OHSS. In this review, I consider whether OHSS still remains a clinical problem in modern reproductive practice, where we are able to apply these advances in routine practice. Specifically, I use the term ‘modern reproductive medicine practice’ to include the following:

1. Ovarian stimulation using FSH doses based on ovarian reserve tests (anti-Mullerian hormone and/or antra follicle count).

2. Routine gonadotropin-releasing hormone antagonist (GnRH-ant) use, particularly in women with high ovarian reserve.

3. Gonadotropin-releasing hormone agonist (GnRH-a) trigger in women at increased risk of OHSS.

4. Freeze-all (cryopreservation of all embryos) in women at increased risk of OHSS.

This review addresses whether OHSS is still a significant problem even with the application of the above measures, and goes on to consider aspects of OHSS where a challenge persists.

INCIDENCE

To determine whether OHSS is a problem in modern practice, one must begin with how frequently it occurs in clinical practice. Unfortunately, we are not able to answer this question in a convincing way. A number of studies have examined the incidence of OHSS in individual centres over a limited study period, and are summarised in an excellent review.^[2] Considering IVF alone, ‘moderate’ OHSS occurred in 3% to 6% and ‘severe’ OHSS in 0.1% to 2% of all cycles.

These numbers provide our best estimates for the incidence of OHSS before the introduction of the innovations listed above, which constitute modern practice. Subsequent studies are fewer in number. Following the introduction of GnRH-ant, the incidence of OHSS requiring hospitalisation in 2524 consecutive IVF cycles was 2.1%.^[3] Importantly, final follicular maturation occurred with 10,000 IU of human chorionic gonadotropin (hCG). A more recent retrospective study of 1492 consecutive cycles using GnRH-ant and a liberal use of GnRH-a trigger and freeze-all found an incidence of moderate or severe OHSS of 1.6%.^[4]

Ideally, data on the incidence of OHSS should be obtained from national or global sources with mandatory reporting. This does not currently exist to our knowledge, with the exception of the requirement of the UK Human Fertilisation and Embryology Authority (HFEA) for clinics to report all cases of ‘severe’ or ‘critical’ OHSS. HFEA data show a stable annual incidence of 0.1% to 0.2% of all IVF cycles.^[5] A criticism that can be made of the HFEA data is that if clinics are not aware of cases of OHSS looked after by other providers, they would be unable to report them resulting in under-reporting.

One approach to overcome the problem of underreporting is to use hospital admission data. Rotshenker-Olshinka et al.^[6] looked at hospital admissions with a diagnosis of OHSS in the Health-Care Cost and Utilization Project-Nationwide Inpatient Sample database (HCUP-NIS) over 11 years (2004–2014), and found an incidence of 1.2 to 2.0 OHSS admissions per 10,000 women hospitalized per year. Further, the incidence measured in this way declined between 2004 and 2014, albeit with a plateau after 2008.

A Danish study examined hospital admissions with a diagnosis of OHSS over 17 years (2001–2017) and found 2261 (1.2%) women admitted for OHSS from 186,168 stimulated IVF cycles, yielding an annual incidence of OHSS of 0.9% to 1.4% of cycles, with no overall change over time.^[7]

Based on these studies, it is reasonable to say that, even with modern reproductive medicine practice, OHSS still remains a significant problem for our patients. However, despite the availability of these data, we are left in the dark about the true incidence of clinically significant OHSS. While hospital admission is no doubt a significant event for the patient and utilises significant healthcare resources, but it does not capture the full spectrum of morbidity and ill health caused by OHSS. Increasingly, even severe OHSS can be safely managed in an outpatient setting, which may further reduce the usefulness of hospital admission data in understanding the true impact of OHSS on our patients.