Preventing Ovarian Hyperstimulation Syndrome

A potentially severe and life-threatening complication of infertility treatment is Ovarian Hyperstimulation Syndrome (OHSS), a disease that almost exclusively occurs as the result of infertility treatment. Luckily, OHSS is no longer as common a consequence of IVF as in the past, since scientific progress has made it easier to avoid. However, despite this, identifying in advance patients who may experience it can still be quite difficult. OHSS is estimated to complicate 5-10% of IVF treatment cycles. It can vary in degree, from mild to severe, ranging from mild discomfort to life-threatening illness. Much of OHSS can be managed in an out-patient setting, like IVF, but rare cases will require admission to hospital intensive care. Luckily, this extreme is now quite rare, occurring typically in less than 1% of cases.

Symptoms of mild hyperstimulation include bloating, abdominal discomfort, temporary weight gain and enlargement of the ovaries. Severe hyperstimulation can lead to kidney failure, pulmonary embolism and permanent injury.

When OHSS occurs, hormone mediators associated with ovarian stimulation have surprising consequences. Blood vessels become, “leaky,” or more permeable, allowing fluid to shift out of the blood supply and into the interstitial or “middle tissues” where it accumulates due to osmosis. This has two major effects: fluid becomes trapped outside of the blood vessels and the blood becomes more viscous. Blood consists essentially of two components, a mixture of solids diluted in liquid. The serum, or liquid component, carries the solid components, which includes red and white blood cells and proteins, much in the same way like a river that carries along plant life and silt. When fluid “leaks” out of the bloodstream, it leaves behind the solid components of blood. When these components are increasingly concentrated, blood flow slows and is more prone to initiating blood clots or thrombi, which can block the flow of blood and cause life-threatening harm. Fluid accumulation outside the vessels leads to edema, or swelling of those tissues. In the abdominal cavity, fluid accumulation increases the work load of the diaphragm because the diaphragm has to push against the abdominal organs and fluid to inflate the lungs, and so makes it harder to take deep breaths. Fluid accumulation in the lungs can, in its severest form, interfere with oxygen “exchange” to the red blood cells, essentially causing a phenomenon akin to drowning.

The first step to preventing OHSS is to recognize that it is possible in all patients undergoing ovarian stimulation treatments and to identify risk factors that are associated with its occurrence. For example, young age, a high follicle count, a high Anti-Müllerian Hormone (AMH) level, and the presence of Polycystic Ovary Syndrome (PCOS) are all known to be risk factors for OHSS. Additionally, a robust response to stimulation medications with resultingly high estrogen levels, retrieval procedures resulting in large numbers of eggs retrieved, and a previous treatment in which OHSS occurred are all strongly associated with OHSS.

Unfortunately, the desire to achieve a high egg yield from stimulation makes prevention of OHSS trickier, since physicians are tasked with trying to make treatment efficient, but safe. Additionally, patient desire to avoid repeating treatment by having many eggs is counterbalanced by their desire to avoid feeling miserable from the treatment itself! This can make a fine line to tread.

Choosing an appropriate stimulation dosage that isn’t too high for a patient is the primary step to avoid hyperstimulation risk, which increases as the stimulation treatment days progress. Next, frequent monitoring of estrogen levels, which can be a warning sign for at-risk patients, is extremely important. Monitoring of ovarian response by measuring estrogen levels and the number and size of growing follicles allows the physician to adjust medication doses, as needed. Accurate dosing, through the use of patient-friendly dosing devices, such as injection, “pens,” and consistency between manufacturing lots of hormones help ensure that patients receive the prescribed dose of medications intended for their treatments. And, finally, the, “trigger,” medication that initiates the final maturation step and makes an egg retrieval possible can be adjusted to modify the risk of OHSS. A higher trigger dose can provoke a larger release of the hormone signals that contribute to OHSS, so using the minimal effective dose can help mitigate risk. Additionally, the time that the trigger medication remains circulating in the body can contribute to risk by continuing to stimulate the factors that cause OHSS. Human Chorionic Gonadotropin (hCG) is often used because it mimics the actions of Luteinizing Hormone (LH), which is the body’s natural trigger of ovulation. hCG was once the primary means to initiate the final step before retrieval, but it has a long duration of action or, “half-life,” before it is excreted from the body. Luteinizing Hormone is much shorter acting and would need to be injected frequently in order to achieve the same effect compared to a convenient single dose of hCG.

Currently, the use of, “dual,” trigger regimens have become popular because of their efficacy and safety. The dual trigger consists of a low dose of long-acting hCG and a second hormone, gonadotropin releasing hormone (GnRH, leuprolide acetate or, “Lupron,”), which provokes the pituitary gland to release a burst of LH. The short burst of natural LH and the low-dose of long-acting hCG combine to provide an effective trigger, but with reduced risks of OHSS. In some cases, it may be appropriate to give a, “Lupron-only,” trigger, if the risks associated with the long acting hCG are too concerning. Unfortunately, the combination or Lupron-only trigger cannot be used in all situations, such as when GnRH is already in use during the stimulation phase of the treatment cycle.

Post-trigger OHSS risk can be mitigated also: use of the medication cabergoline can decrease the production of the hormone VEGF, or vascular-endothelial growth factor, which is the primary driver of the “leaky vessel” effect. Also, ironic for infertility patients, avoiding pregnancy can reduce risk: embryo implantation and growth is associated with increasing levels of hCG, which is produced by the embryo’s rapidly dividing cells, and contributes to the effect initiated by the trigger medications, effectively similar to injecting hCG daily. Forgoing an embryo transfer days after the egg retrieval can therefore reduce the risk of OHSS. In many cases, with modern IVF, embryo transfers are not performed in the same cycle as the egg retrieval so as to allow for embryo biopsy and preimplantation genetic testing of embryos, which has secondarily had the effect of decreasing OHSS risk. But any treatment cycle can be converted to a, “freeze all,” cycle, in which the embryos are withheld until the OHSS risk has subsided.

Patient education about the risks and drivers of OHSS are an integral part of any treatment program because patient participation in the treatment plan can help to avoid the occurrence of OHSS. Understanding that, “maximal stimulation,” of the ovaries is not the goal of infertility treatment, but, rather, “optimal stimulation,” that leads to efficient and safe treatment and good outcomes, is of paramount importance. Patients should understand that aiming to achieve the highest yield and most robust response may not provide the best outcome of treatment, even when the eggs retrieved are not intended for immediate use, but are to be cryopreserved.

Ironically, the best outcomes of ovarian stimulation may, in some ways, pass unnoticed: optimized treatment that prevents the occurrence of OHSS is likely underappreciated, except by practitioners of infertility treatments. Advancements in understanding the causes of OHSS, the availability of techniques to modify the risk of its occurrence, and experienced practitioners trained in the proper management of patients undergoing ovarian stimulation procedures have thankfully made the likelihood of the severest forms of OHSS rare and have made fertility treatments very safe.

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